Therapeutic use of antibodies to hgf

ABSTRACT

The present invention is directed to antibodies and fragments thereof (especially chimeric and humanized) having binding specificity for HGF and their use in therapy and diagnosis. These antibodies inhibit or block HGF-associated activities including HGF&#39;s effects on cell proliferation, invasion, angiogenesis, metastasis and fibrosis. Particularly the antibodies may be used as a monotherapy or in combination therapies in treating cancer, other proliferative disorders and other conditions wherein inhibition of HGF and/or the HGF/HGF-R (c-met) interaction is desired.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.13/803,768, filed Mar. 14, 2013, the disclosure of which is hereinincorporated by reference in its entirety.

SEQUENCE LISTING

The sequence listing in the file named “43257o4204.txt” having a size of645,711 bytes that was created May 11, 2015 is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention pertains to antibodies and fragments thereof, preferablyhigh affinity or avidity antibodies having binding specificity toHepatocyte Growth Factor (hereinafter “HGF”). More specifically, theinvention also pertains to methods of screening for diseases anddisorders associated with HGF, and methods of preventing or treatingdiseases and disorders associated with HGF by administering saidantibodies or fragments thereof.

2. Description of Related Art

Hepatocyte Growth Factor (HGF) (also known as scatter factor (SF) isproduced as a single-chain inactive precursor that is cleaved by serineproteases into two chains that are linked by a disulfide bond.(Abounader, R., et al., Neuro-Oncology, 7:436-451 (2005)). The geneencoding HGF is located on chromosome 7q21.1. The biologically activeform of HGF is a heterodimer composed of a 69-kDa α-chain and a 34-kDaβ-chain. The α-chain contains an N-terminal hairpin domain and 4 kringledomains, while the β-chain contains a serine protease-like domain havingno enzymatic activity. Id.

Human Hepatocyte Growth Factor (HGF) is a multifunctional heterodimericpolypeptide produced by mesenchymal cells. HGF has been shown tostimulate angiogenesis, morphogenesis and motogenesis, as well as thegrowth and scattering of various cell types (Bussolino et al., J. Cell.Biol. 119: 629, 1992; Zarnegar and Michalopoulos, J. Cell. Biol.129:1177, 1995; Matsumoto et al, Ciba. Found. Symp. 212:198, 1997;Birchmeier and Gherardi, Trends Cell. Biol. 8:404, 1998; Xin et al., Am.J. pathol. 158:1111, 2001). The pleiotropic activities of HGF aremediated through its receptor, a transmembrane tyrosine kinase encodedby the proto-oncogene c-met. In addition to regulating a variety ofnormal cellular functions, HGF and its receptor c-met have been shown tobe involved in the initiation, invasion and metastasis of tumors(Jeffers et al., J. Mol. Med. 74:505, 1996; Comoglio and Trusolino, J.Clin. Invest. 109:857, 2002). HGF/c-met are coexpressed, oftenover-expressed, on various human solid tumors including tumors derivedfrom lung, colon, rectum, stomach, kidney, ovary, skin, multiple myelomaand thyroid tissue (Prat et al., Int. J. Cancer 49:323, 1991; Chan etal., Oncogene 2:593, 1988; Weidner et al., Am. J. Respir. Cell Mol.Biol, 8:229, 1993; Derksen et al., Blood 99:1405, 2002). HGF acts as anautocrine (Rong et al., Proc. Natl. Acad. Sci. USA 91:4731, 1994;Koochekpour et al., Cancer Res. 57:5391, 1997) and paracrine growthfactor (Weidner et al., Am. J. Respir. Cell Mol. Biol. 8:229, 1993) andanti-apoptotic regulator (Gao et al., J. Biol. Chem. 276:47257, 2001)for these tumors.

HGF is a 102 kDa protein with sequence and structural similarity toplasminogen and other enzymes of blood coagulation (Nakamura et al.,Nature 342:440, 1989; Weidner et al., Am. J. Respir. Cell. Mol. Biol.8:229, 1993, each of which is incorporated herein by reference). HumanHGF is synthesized as a 728 amino acid precursor (preproHGF), whichundergoes intracellular cleavage to an inactive, single chain form(proHGF) (Nakamura et al., Nature 342:440, 1989: Rosen et al., J. Cell.Biol. 127:1783, 1994). Upon extracellular secretion, proHGF is cleavedto yield the biologically active disulfide-linked heterodimeric moleculecomposed of an alpha.subunit and beta-subunit (Nakamura et al., Nature342:440, 1989; Naldini et al., EMBO J. 11:4825, 1992). The alpha-subunitcontains 440 residues (69 kDa with glycosylation), consisting of theN-terminal hairpin domain and four kringle domains. The beta-subunitcontains 234 residues (34 kDa) and has a serine protease-like domain,which lacks proteolytic activity. Cleavage of HGF is required forreceptor activation, but not for receptor binding (Hartmann et al.,Proc. Natl. Acad. Sci. USA 89:11574, 1992; Lokker et al., J. Biol. Chem.288:17145, 1992). HGF contains 4 putative N-glycosylation sites, 1 inthe alpha-subunit and 3 in the beta-subunit. HGF has 2 unique cellspecific binding sites: a high affinity (Kd=2×10⁻¹⁰ M) binding site forthe c-met receptor and a low affinity (Kd=10.sup.-9 M) binding site forheparin sulfate proteoglycans (HSPG), which are present on the cellsurface and extracellular matrix (Naldinl et al., Oncogene 6:501, 1991;Bardelii et al., J. Biotechnol. 37:109, 1994; Sakata et al., J. Biol.Chem., 272:9457, 1997).

c-met is a member of the class IV protein tyrosine kinase receptorfamily. The full length c-met gene was cloned and identified as thec-met proto-oncogene (Cooper et al., Nature 311:29, 1984; Park et al.,Proc. Natl. Acad. Sci. USA 84:6379, 1987). The c-met receptor isinitially synthesized as a single chain, partially glycosylatedprecursor, p170_((MET)) (Park et al., Proc. Natl. Acad. Sci. USA84:6379, 1987; Giordano et al., Nature 339:155, 1989; Giordano et al.,Oncogene 4:1383, 1989; Bardelli et al., J. Biotechnol. 37:109, 1994).Upon further glycosylation, the protein is proteolytically cleaved intoa heterodimeric 190 kDa mature protein (1385 amino acids), consisting ofthe 50 kDa alpha-subunit (residues 1-307) and the 145 kDa beta-subunit.The cytoplasmic tyrosine kinase domain of the beta-subunit is involvedin signal transduction.

Several different approaches have been investigated to obtain HGFinhibitors or HGF antagonists. Such inhibitors include truncated HGFproteins such as NK1 (N terminal domain plus kringle domain 1: Lokker etal., J. Biol. Chem. 268:17145, 1993); NK2 (N terminal domain pluskringle domains 1 and 2: Chan et al., Science 254:1382, 1991); and NK4(N-terminal domain plus four kringle domains), which was shown topartially inhibit the primary growth and metastasis of murine lung tumorLLC in a nude mouse model (Kuba et al., Cancer Res. 60:6737, 2000).

As another approach, Dodge (Master's Thesis, San Francisco StateUniversity, 1998) generated antagonist anti-c-met monoclonal antibodies(mAbs). One mAb, 5D5, exhibited strong antagonistic activity in ELISA,but induced a proliferative response of c-met-expressing BAF-3 cells,presumably due to dimerization of the membrane receptors. For thisreason, a single domain form of the anti-c-met mAb 5D5 has beendeveloped as an antagonist (Nguyen et al., Cancer Gene Ther, 10:840,2003).

Cao et al., Proc. Natl. Acad. Sci. USA 98:7443, 2001, reported that theadministration of a cocktail of three anti-HGF mAbs, which were selectedbased upon their ability to inhibit the scattering activity of HGF invitro, were able to inhibit the growth of human tumors in the xenograftnude mouse model.

More recently, neutralizing (inhibitory) anti-HGF mAbs have beenreported including L2G7 (Kim et al., Clin Cancer Res 12:1292, 2006, WO2005/107800, and U.S. Pat. No. 7,220,410 HuL2G7 (WO 2007/115049, thehuman mAbs described in WO 2005/17107, and the HGF binding proteinsdescribed in WO 2007/143090 or WO 2007/143098. It has also been reportedthat the anti-HGF mAb L2G7, when administered systemically, can stronglyinhibit growth or even induce regression of orthotopic (intracranial)glioma xenografts and prolong animal survival (Kim et al., op. cit andWO 2006/130773).

As disclosed herein, HGF promotes the growth and/or scattering ofvarious cell types, and has been shown to be involved in the promotionof angiogenesis, the inhibition of cell growth, and the conversion froma mesenchymal to an epithelial phenotype. Also, both HGF and c-met areexpressed in a wide variety of human tumors, and their expression levelsis sometimes correlated with poor prognosis. Moreover HGF is believed toplay a role in the development of a multitude of diseases and disorders,including but not limited to the development and metastasis of numerouscancers, and the development of macular degeneration. Due to theperceived involvement of HGF in a wide range of diseases and disorders,there remains a need in the art for HGF antagonists and compositionscontaining and methods useful for preventing or treating diseasesassociated with HGF, as well as methods of screening to identifypatients having diseases or disorders associated with HGF. Particularlypreferred are anti-HGF antagonists and compositions containing whicheffectively inhibit at least one HGF associated biological activity andwhich elicit minimal or no adverse reactions when administered to apatient. The present invention achieves this objective.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to specific antibodies and fragmentsthereof having binding specificity for HGF, in particular antibodieshaving desired epitopic specificity, high affinity or avidity and/orfunctional properties and the use thereof in therapy and diagnostics.Specifically, the invention provides chimeric or humanized antibodiesand fragments thereof capable of binding to HGF and/or the HGF-HGFR(c-met) complex. Another embodiment of this invention relates to theantibodies described herein, comprising the sequences of the V_(H),V_(L) and CDR polypeptides described herein, and the polynucleotidesencoding them. In more specific embodiments of the invention theseantibodies will possess binding affinities (Kd's) less than 500picomolar and/or K_(off) values less than or equal to 10⁻⁴ S⁻¹.

More particularly, the invention provides rabbit antibodies andhumanized and chimeric antibodies derived therefrom specific to HGF aswell as antibody fragments specific to HGF which include e.g., Fab′,F(ab′)₂, Fv, scFv fragments, SMIPs (small moleculeimmunopharmaceuticals), camelbodies, nanobodies, monovalent antibodiessuch as MetMab like antibodies, and IgNAR which may be used in therapyand diagnostics.

Further, the invention provides nucleic acids and host cells containingthat encode for and result in the expression of the subject anti-HGFantibodies, i.e., rabbit antibodies and antibody fragments and modifiedforms thereof including by way of example humanized and chimericantibodies derived therefrom as well as antibody fragments which includee.g., Fab′, F(ab′)₂, Fv, scFv fragments, SMIPs (small moleculeimmunopharmaceuticals), camelbodies, nanobodies, monovalent antibodiessuch as MetMab like antibodies, and IgNAR.

Also the invention relates to expression systems for the manufacture ofthe inventive anti-HGF antibodies, including yeast, fungi, mammalian,and other cells useful for the manufacture of antibodies and antibodyfragments.

Also, the invention relates to novel antibodies and antibody fragmentsthat specifically bind to human HGF which compete with and/orspecifically bind to the same or overlapping epitope(s) on HGF as any ofthe anti-HGF antibodies and antibody fragments exemplified herein.

Further, the invention provides anti-HGF antibodies and antibodyfragments that partially or fully neutralize HGF, and which partially orcompletely inhibit one or more biological activities of HGF such as theability of HGF to cause fibrosis or the scattering, proliferation,angiogenesis, chemotaxis of cells.

The invention further pertains to the in vivo use of the subjectanti-HGF antibodies and antibody fragments alone or in association withother active agents or drugs for blocking, inhibiting or neutralizingHGF or at least one activity of HGF and/or for inhibiting or blockingthe HGF/HGF-R (c-met) interaction or inhibiting c-met activation.

The invention further specifically pertains to the in vivo use of thesubject anti-HGF antibodies and antibody fragments alone or inassociation with other active agents or drugs.

The invention further specifically pertains to the, anti-HGF antibodiesdescribed herein, or fragments thereof, for ameliorating or reducing thesymptoms of, or treating, or preventing, the following non-limitinglisting of proliferative, non-proliferative diseases and disorders suchas cancers, including ovarian cancer, breast cancer, lung cancer (smallcell or non-small cell), colon and colorectal cancer, prostate cancer,pancreatic cancer, renal cancer, gastric cancer, liver cancer, bladdercancer, thyroid cancer, endometrial cancer, head-and-neck tumors,melanoma, sarcomas, leukemias; lymphomas; and brain tumors (e.g.,glioblastomas), of children or adults; macular degeneration; Alzheimer'sdisease; and malarial infection. In a preferred embodiment, the diseaseis selected from a cancer or macular degeneration.

The invention further pertains to medicaments for the therapeutic and/orprophylactic treatment of different diseases such as a cancer, a tumor,a cell proliferative disorder, an immune (such as autoimmune) disorderand/or an angiogenesis-related disorder. In another embodiment of theinvention, the invention provides use of a nucleic acid of the inventionin the preparation of a medicament for the therapeutic and/orprophylactic treatment of a disease, such as a cancer, a tumor, a cellproliferative disorder, an immune (such as autoimmune) disorder and/oran angiogenesis-related disorder.

The invention further pertains to the use of an expression vector of theinvention in the preparation of a medicament for the therapeutic and/orprophylactic treatment of a disease, such as a cancer, a tumor, a cellproliferative disorder, an immune (such as autoimmune) disorder and/oran angiogenesis-related disorder. In another embodiment of theinvention, the invention provides use of an of a host cell of theinvention in the preparation of a medicament for the therapeutic and/orprophylactic treatment of a disease, such as a cancer, a tumor, a cellproliferative disorder, an immune (such as autoimmune) disorder and/oran angiogenesis-related disorder. In another embodiment of theinvention, the invention provides the use of an article of manufactureof the invention in the preparation of a medicament for the therapeuticand/or prophylactic treatment of a disease, such as a cancer, a tumor, acell proliferative disorder, an immune (such as autoimmune) disorderand/or an angiogenesis-related disorder. The invention further pertainsto the use of a kit of the invention in the preparation of a medicamentfor the therapeutic and/or prophylactic treatment of a disease, such asa cancer, a tumor, a cell proliferative disorder, an immune (such asautoimmune) disorder and/or an angiogenesis-related disorder.

The invention further specifically pertains to modulating disease statesassociated with dysregulation of the HGF/c-met signaling axis andthereby modulating at least one of cell proliferation, invasion,metastasis and angiogenesis.

Methods of the invention can be used to affect any pathological stateassociated with dysregulation of the HGF/c-met signaling which includeschronic and acute disorders or diseases including those pathologicalconditions which predispose the mammal to the disorder in question.Non-limiting examples of disorders to be treated herein includemalignant and benign tumors; non-leukemias and lymphoid malignancies;neuronal, glial, astrocytal, hypothalamic and other glandular,macrophagal, epithelial, stromal and blastocoelic disorders; andinflammatory, immunologic and other angiogenesis-related disorders.carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particularexamples of such cancers include squamous cell cancer, small-cell lungcancer, non-small cell lung cancer, adenocarcinoma of the lung, squamouscarcinoma of the lung, cancer of the peritoneum, hepatocellular cancer,gastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, colorectal cancer, endometrial or uterinecarcinoma, salivary gland carcinoma, kidney cancer, liver cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma andvarious types of head and neck cancer; disorders involving dysregulationof angiogenesis including both non-neoplastic and neoplastic conditionssuch as the cancers described herein and non-neoplastic disordersincluding but are not limited to undesired or aberrant hypertrophy,arthritis, rheumatoid arthritis (RA), psoriasis, psoriatic plaques,sarcoidosis, atherosclerosis, atherosclerotic plaques, diabetic andother proliferative retinopathies including retinopathy of prematurity,retrolental fibroplasia, neovascular glaucoma, age-related maculardegeneration, diabetic macular edema, corneal neovascularization,corneal graft neovascularization, corneal graft rejection,retinal/choroidal neovascularization, neovascularization of the angle(rubeosis), ocular neovascular disease, vascular restenosis,arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma,thyroid hyperplasias (including Grave's disease), corneal and othertissue transplantation, chronic inflammation, lung inflammation, acutelung injury/ARDS, sepsis, primary pulmonary hypertension, malignantpulmonary effusions, cerebral edema (e.g., associated with acutestroke/closed head injury/trauma), synovial inflammation, pannusformation in RA, myositis ossificans, hypertropic bone formation,osteoarthritis (OA), refractory ascites, polycystic ovarian disease,endometriosis, 3rd spacing of fluid diseases (pancreatitis, compartmentsyndrome, burns, bowel disease), uterine fibroids, premature labor,chronic inflammation such as IBD (Crohn's disease and ulcerativecolitis), renal allograft rejection, inflammatory bowel disease,nephrotic syndrome, undesired or aberrant tissue mass growth(non-cancer), hemophilic joints, hypertrophic scars, inhibition of hairgrowth, Osler-Weber syndrome, pyogenic granuloma retrolentalfibroplasias, scleroderma, trachoma, vascular adhesions, synovitis,dermatitis, preeclampsia, ascites, pericardial effusion (such as thatassociated with pericarditis), and pleural effusion.

In certain embodiments, a specific binding agent to HGF according to theinvention is used with one or more other therapeutic agents to treatvarious cancers. In certain embodiments, a specific binding agent to HGFis used with one or more particular therapeutic agents to treat orprevent malaria. In certain embodiments, a specific binding agent to HGFaccording to the invention is used with one or more particulartherapeutic agents to treat or prevent proliferative diabeticretinopathy. In certain embodiments, in view of the condition and thedesired level of treatment, two, three, or more agents may beadministered. In certain embodiments, such agents may be providedtogether by inclusion in the same formulation. In certain embodiments,such agents and a specific binding agent to HGF according to theinvention may be provided together by inclusion in the same formulation.In certain embodiments, such agents may be formulated separately andprovided together by inclusion in a treatment kit. In certainembodiments, such agents and a specific binding agent to HGF may beformulated separately and provided together by inclusion in a treatmentkit. In certain embodiments, such agents may be provided separately.

The invention also contemplates conjugates of anti-HGF antibodies andbinding fragments thereof conjugated to one or more functional ordetectable moieties. The invention also contemplates methods of makingsaid chimeric or humanized anti-HGF or anti-HGF/HGF-R complex antibodiesand binding fragments thereof. In one embodiment, binding fragmentsinclude, but are not limited to, Fab, Fab′, F(ab′)₂, Fv, scFv fragments,SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies,and IgNAR.

Embodiments of the invention further pertain to the use of anti-HGFantibodies for the diagnosis, assessment and treatment of diseases anddisorders associated with HGF or aberrant expression thereof. Theinvention also contemplates the use of fragments of anti-HGF antibodiesfor the diagnosis, assessment and treatment of diseases and disordersassociated with HGF or aberrant expression thereof. Other embodiments ofthe invention relate to the production of anti-HGF antibodies inrecombinant host cells, preferably diploid yeast such as diploid Pichiaand other yeast strains.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab1.

FIG. 2 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab2.

FIG. 3 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab7.

FIG. 4 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab8.

FIG. 5 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab9.

FIG. 6 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab10.

FIG. 7 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab12.

FIG. 8 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab14.

FIG. 9 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab19.

FIG. 10 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab21.

FIG. 11 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab23.

FIG. 12 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab24.

FIG. 13 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab25.

FIG. 14 provides the human-HGF ELISA binding data obtained following theprotocol in Example 8 infra for antibody Ab28.

FIG. 15 provides the response of subcutaneous U-87MG glioma to treatmentwith a negative control antibody, Ab10 and Ab12 (10 mg/kg/inj) obtainedfollowing the protocol corresponding to FIGS. 15 and 16 in Example 10infra.

FIG. 16 provides the survival proportions curve of subcutaneous U-87MGglioma treated with either a negative control antibody, or Ab10 or Ab12(10 mg/kg/inj) obtained following the protocol for FIGS. 15 and 16 inExample 10 infra.

FIG. 17 provides the response of subcutaneous U-87MG glioma to treatmentwith increasing doses of Ab8 (10, 2.5 and 0.25 mg/kg/inj) or a negativecontrol antibody (10 mg/kg/inj) obtained following the protocolcorresponding to FIGS. 17 and 18 described in Example 10 infra.

FIG. 18 provides the survival proportions curve of subcutaneous U-87MGglioma treated with either increasing doses of Ab8 (10, 2.5 and 0.25mg/kg/inj) or a negative control antibody (10 mg/kg/inj) obtainedfollowing the experimental protocol corresponding to FIGS. 17 and 18described in Example 10 infra.

FIG. 19 provides the response of subcutaneous U-87MG glioma to treatmentwith increasing doses of Ab10 (10, 2.5 and 0.25 mg/kg/inj) or a negativecontrol antibody (10 mg/kg/inj) obtained following the protocolcorresponding to FIGS. 19 and 20 described in Example 10 infra.

FIG. 20 provides the survival proportions curve of subcutaneous U-87MGglioma treated with either increasing doses of Ab10 (10, 2.5 and 0.25mg/kg/inj) or a negative control antibody (10 mg/kg/inj) obtainedfollowing the protocol corresponding to FIGS. 19 and 20 in Example 10infra.

FIG. 21 provides the response of subcutaneous U-87MG glioma to treatmentwith increasing doses of Ab28 (30, 10, and 2.5 mg/kg/inj) or a negativecontrol antibody (30 mg/kg/inj) obtained following the experimentalprotocol corresponding to FIGS. 21 and 22 described in Example 10 infra.

FIG. 22 provides the survival proportions curve of subcutaneous U-87MGglioma treated with either increasing doses of Ab28 (30, 10, and 2.5mg/kg/inj) or a negative control antibody (30 mg/kg/inj) obtainedfollowing the experimental protocol corresponding to FIGS. 21 and 22described in Example 10 infra.

FIG. 23 contains data from experiments showing the inhibition ofhuman-HGF driven phosphorylation of Y1234/35, Y1003 and Y1349 of c-metby Ab8 using PC-3 cells (prostate adenocarcinoma) following theexperimental protocol described in Example 11 infra.

FIGS. 24-37 respectively contain the results of experiments assaying theeffect of different anti-HGF antibodies according to the invention (Ab1,Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25 andAb28) on human-HGF driven cell proliferation of 4mBr-5 cells (rhesusmonkey bronchial epithelial cells) following the experimental protocolin Example 12 infra.

FIG. 38 contains the results of experiments assaying the effect of ananti-HGF antibody (Ab8) according to the invention on human-HGF drivencell invasion of DBTRG cells (human glioblastoma) using Matrigelchambers following the experimental protocol described in Example 13infra.

FIGS. 39A-39G provide the polypeptide sequences of the full-length heavychain for antibodies Ab1-Ab21, and Ab23-28 aligned by their frameworkregions (FR), complementarity determining regions (CDRs), and constantregions.

FIGS. 40A-40D provide the polypeptide sequences of the full-length lightchain for antibodies Ab1-Ab21 and Ab23-28 aligned by their frameworkregions (FR), complementarity determining regions (CDRs), and constantregions.

FIG. 41A-41S provide the polynucleotide sequences encoding thefull-length heavy chain for antibodies Ab1-Ab21 and Ab23-28 aligned bytheir framework regions (FR), complementarity determining regions(CDRs), and constant regions.

FIG. 42A-42J provide the polynucleotide sequences encoding thefull-length light chain for antibodies Ab1-Ab21 and Ab23-28 aligned bytheir framework regions (FR), complementarity determining regions(CDRs), and constant regions.

FIG. 43 provides the polypeptide sequence coordinates for the variableregion and complementarity determining regions (CDRs) of the heavy chainfor antibodies Ab1-Ab21 and Ab23-28.

FIG. 44 provides the polypeptide sequence coordinates for the constantregion and framework regions (FR) of the heavy chain for antibodiesAb1-Ab21, and Ab23-28.

FIG. 45 provides the polypeptide sequence coordinates for the variableregion and complementarity determining regions (CDRs) of the light chainfor antibodies Ab1-Ab21 and Ab23-28.

FIG. 46 provides the polypeptide sequence coordinates for the constantregion and framework regions (FR) of the light chain for antibodiesAb1-Ab21, and Ab23-28.

FIG. 47 provides the polynucleotide sequence coordinates for thevariable region and complementarity determining regions (CDRs) of theheavy chain for antibodies Ab1-Ab21 and Ab23-28.

FIG. 48 provides the polynucleotide sequence coordinates for theconstant region and framework regions (FR) of the heavy chain forantibodies Ab1-Ab21 and Ab23-28.

FIG. 49 provides the polynucleotide sequence coordinates for thevariable region and complementarity determining regions (CDRs) of thelight chain for antibodies Ab1-Ab21, and Ab23-28.

FIG. 50 provides the polynucleotide sequence coordinates for theconstant region and framework regions (FR) of the light chain forantibodies Ab1-Ab21, and Ab23-28.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Definitions

It is to be understood that this invention is not limited to theparticular methodology, protocols, cell lines, animal species or genera,and reagents described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention which will be limited only by the appended claims.

As used herein the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the protein” includes reference to one or more proteinsand equivalents thereof known to those skilled in the art, and so forth.All technical and scientific terms used herein have the same meaning ascommonly understood to one of ordinary skill in the art to which thisinvention belongs unless clearly indicated otherwise.

Hepatocyte Growth Factor (HGF): As used herein, HGF encompasses not onlythe following preproprotein amino acid sequence available as NCBIReference Sequence: NP_(—)000592.3 (Homo sapiens HGF isoform 1preproprotein):

MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS (SEQ ID NO: 1081), but also any pro-, mature, soluble,and/or membrane-bound forms of this HGF amino acid sequence, as well asmutants (mutiens), splice variants, isoforms, orthologs, homologues andvariants of this sequence.

Hepatocyte Growth Factor Receptor (HGF-R):

As used herein, the terms “HGF-R” and “c-met” refer to a cellularreceptor for hepatocyte growth factor (HGF), which typically includes anextracellular domain, a transmembrane domain and an intracellulardomain, as well as variants and fragments thereof which retain theability to bind HGF, and includes the polypeptide molecule thatcomprises the full-length, native amino acid sequence. Human HepatocyteGrowth Factor (HGF) is a multifunctional heterodimeric polypeptideproduced by mesenchymal cells. HGF has been shown to stimulateangiogenesis, morphogenesis and motogenesis, as well as the growth andscattering of various cell types (Bussolino et al., J. Cell. Biol. 119:629, 1992; Zarnegar and Michalopoulos, J. Cell. Biol. 129:1177, 1995;Matsumoto et al., Ciba. Found. Symp. 212:198, 1997; Birchmeier andGherardi, Trends Cell. Biol. 8:404, 1998; Xin et al. Am. J. Pathol.158:1111, 2001). The pleiotropic activities of HGF are mediated throughits receptor, a transmembrane tyrosine kinase encoded by theproto-oncogene c-met. In addition to regulating a variety of normalcellular functions, HGF and its receptor c-met have been shown to beinvolved in the initiation, invasion and metastasis of tumors (Jefferset al., J. Mol. Med. 74:505, 1996; Comoglio and Trusolino, J. Clin.Invest. 109:857, 2002). HGF/c-met are coexpressed, often over-expressed,on various human solid tumors including tumors derived from lung, colon,rectum, stomach, kidney, ovary, skin, multiple myeloma and thyroidtissue (Prat et al., Int. J. Cancer 49:323, 1991; Chan et al., Oncogene2:593, 1988; Weidner et al., Am. J. Respir. Cell. Mol. Biol. 8:229,1993; Derksen et al., Blood 99:1405, 2002). HGF acts as an autocrine(Rong et al., Proc. Natl. Acad. Sci. USA 91:4731, 1994; Koochekpour etal., Cancer Res. 57:5391, 1997) and paracrine growth factor (Weidner etal., Am. J. Respir. Cell. Mol. Biol. 8:229, 1993) and anti-apoptoticregulator (Gao et al., J. Biol. Chem. 276:47257, 2001) for these tumors.HGF is a 102 kDa protein with sequence and structural similarity toplasminogen and other enzymes of blood coagulation (Nakamura et al.,Nature 342:440, 1989; Weidner et al., Am. J. Respir. Cell. Mol. Biol.8:229, 1993). Human HGF is synthesized as a 728 amino acid precursor(preproHGF), which undergoes intracellular cleavage to an inactive,single chain form (proHGF) (Nakamura et al., Nature 342:440, 1989; Rosenet al., J. Cell. Biol. 127:1783, 1994). Upon extracellular secretion,proHGF is cleaved to yield the biologically active disulfide-linkedheterodimeric molecule composed of an a-subunit and n-subunit (Nakamuraet al., Nature 342:440, 1989; Naldini et al., EMBO J. 11:4825, 1992).The alpha-subunit contains 440 residues (69 kDa with glycosylation),consisting of the N-terminal hairpin domain and four kringle domains.The beta-subunit contains 234 residues (34 kDa) and has a serineprotease-like domain, which lacks proteolytic activity. HGF has twounique cell specific binding sites: a high affinity (Kd=2×10⁻¹° M)binding site for the c-met receptor and a low affinity (Kd=10⁻⁹ M)binding site for heparin sulfate proteoglycans (HSPG), which are presenton the cell surface and extracellular matrix (Naldini et al., Oncogene6:501, 1991; Bardelli et al., J. Biotechnol. 37:109, 1994; Sakata etal., J. Biol. Chem., 272:9457, 1997).

“c-met” or “HGF-R” is a member of the class IV protein tyrosine kinasereceptor family. The full length c-met gene was cloned and identified asthe c-met proto-oncogene (Cooper et al., Nature 311:29, 1984; Park etal., Proc. Natl. Acad. Sci. USA 84:6379, 1987). NK2 (a proteinencompassing the N-terminus and first two kringle domains of thealpha-subunit) is sufficient for binding to c-met and activation of thesignal cascade for motility, however the full length protein is requiredfor the mitogenic response (Weidner et al., Am. J. Respir. Cell. Mol.Biol. 8:229, 1993). HSPG binds to HGF by interacting with the N terminusof HGF. HGF/c-met have been reported to play important roles in severalaspects of cancer development such as tumor initiation, invasion,metastasis, regulation of apoptosis and angiogenesis. Several differentapproaches have been investigated to obtain an effective antagonisticmolecule: truncated HGF proteins such as NK1 (N terminal domain pluskringle domain 1; Lokker et al., J. Biol. Chem. 268:17145, 1993), NK2 (Nterminal domain plus kringle domains 1 and 2; Chan et al., Science254:1382, 1991) and NK4 (N-terminal domain plus four kringle domains;Kuba et al., Cancer Res. 60:6737, 2000), anti-c-met mAbs (Dodge,Master's Thesis, San Francisco State University, 1998) and anti-HGF mAbs(Cao et al., Proc. Natl. Acad. Sci. USA 98:7443, 2001).

The term “Neutralizing or Antagonizing Anti-HGF antibody or antibodyfragment” or “HGF Antibody Antagonist” herein refers to a monoclonalantibody (mAb) that binds HGF (i.e., an anti-HGF mAb), wherein thebinding partially or completely inhibits one or more biologicalactivities of HGF (i.e., when the mAb is used as a single agent). Amongthe biological properties of HGF that a neutralizing antibody mayinhibit are the ability of HGF to bind to its c-met receptor, to causethe scattering of certain cell lines such as Madin-Darby canine kidney(MDCK) cells; to stimulate proliferation of (i.e., be mitogenic for)certain cells including hepatocytes, My 1 Lu mink lung epithelial cells,and various human tumor cells; to cause scattering of specific cells, tostimulate angiogenesis, for example as measured by stimulation of humanumbilical vascular endothelial cell (HUVEC) proliferation or tubeformation or by induction of blood vessels when applied to the chickembryo chorioallantoic membrane (CAM), to promote cell invasion ormetastasis, and to promote fibrosis. A “blocking” antibody or an“antagonist” antibody preferably is one which inhibits or reducesbiological activity of the antigen it binds (for e.g., activated HGFbeta chain or site/epitope on c-met to which activated HGF beta binds).Preferred blocking antibodies or antagonist antibodies substantially orcompletely inhibit the biological activity of the antigen.

An “agonist antibody”, as used herein, is an antibody which mimics atleast one of the functional activities of a polypeptide of interest (fore.g., an antibody could provide at least one of the c-met activatingfunctions of activated HGF beta chain).

A “disorder” is any condition that would benefit from treatment with asubstance/molecule or method of the invention. This includes chronic andacute disorders or diseases including those pathological conditionswhich predispose the mammal to the disorder in question. Non-limitingexamples of disorders to be treated herein include malignant and benigntumors; non-leukemias and lymphoid malignancies; neuronal, glial,astrocytal, hypothalamic and other glandular, macrophagal, epithelial,stromal and blastocoelic disorders; and inflammatory, immunologic andother angiogenesis-related disorders.

The terms “cell proliferative disorder” and “proliferative disorder”refer to disorders that are associated with some degree of abnormal cellproliferation. In one embodiment, the cell proliferative disorder iscancer.

“Tumor”, as used herein, refers to all neoplastic cell growth andproliferation, whether malignant or benign, and all pre-cancerous andcancerous cells and tissues. The terms “cancer”, “cancerous”, “cellproliferative disorder”, “proliferative disorder” and “tumor” are notmutually exclusive as referred to herein.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth/proliferation. Examples of cancer include butare not limited to, carcinoma, lymphoma, blastoma, sarcoma, andleukemia. More particular examples of such cancers include squamous cellcancer, small-cell lung cancer, non-small cell lung cancer,adenocarcinoma of the lung, squamous carcinoma of the lung, cancer ofthe peritoneum, hepatocellular cancer, gastrointestinal cancer,pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, livercancer, bladder cancer, hepatoma, breast cancer, colon cancer,colorectal cancer, endometrial or uterine carcinoma, salivary glandcarcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma and various types of head and neckcancer.

As used herein, “treatment” refers to clinical intervention in anattempt to alter the natural course of the individual or cell beingtreated, and can be performed either for prophylaxis or during thecourse of clinical pathology. Desirable effects of treatment includepreventing occurrence or recurrence of disease, alleviation of symptoms,diminishment of any direct or indirect pathological consequences of thedisease, preventing metastasis, decreasing the rate of diseaseprogression, amelioration or palliation of the disease state, andremission or improved prognosis. In some embodiments, antibodies of theinvention are used to delay development of a disease or disorder.

An “effective amount” refers to an amount effective, at dosages and forperiods of time necessary, to achieve the desired therapeutic orprophylactic result. A “therapeutically effective amount” of asubstance/molecule of the invention, agonist or antagonist may varyaccording to factors such as the disease state, age, sex, and weight ofthe individual, and the ability of the substance/molecule, agonist orantagonist to elicit a desired response in the individual. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of the substance/molecule, agonist or antagonist areoutweighed by the therapeutically beneficial effects.

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically but not necessarily, since a prophylacticdose is used in subjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

The terms “cell proliferative disorder” and “proliferative disorder”herein refer to disorders that are associated with some degree ofabnormal cell proliferation. In one embodiment, the cell proliferativedisorder is cancer.

“Tumor”, as used herein, refers to all neoplastic cell growth andproliferation, whether malignant or benign, and all pre-cancerous andcancerous cells and tissues. The terms “cancer”, “cancerous”, “cellproliferative disorder”, “proliferative disorder” and “tumor” are notmutually exclusive as referred to herein.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth/proliferation. Examples of cancer include butare not limited to, carcinoma, lymphoma, blastoma, sarcoma, andleukemia. More particular examples of such cancers include squamous cellcancer, small-cell lung cancer, non-small cell lung cancer,adenocarcinoma of the lung, squamous carcinoma of the lung, cancer ofthe peritoneum, hepatocellular cancer, gastrointestinal cancer,pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, livercancer, bladder cancer, hepatoma, breast cancer, colon cancer,colorectal cancer, endometrial or uterine carcinoma, salivary glandcarcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma and various types of head and neckcancer.

The term “Dysregulation of angiogenesis” herein includes any conditionwherein there is aberrant angiogenesis. This includes bothnon-neoplastic and neoplastic conditions. Neoplastics include but arenot limited to cancers described above. Non-neoplastic disorders includebut are not limited to undesired or aberrant hypertrophy, arthritis,rheumatoid arthritis (RA), psoriasis, psoriatic plaques, sarcoidosis,atherosclerosis, atherosclerotic plaques, diabetic and otherproliferative retinopathies including retinopathy of prematurity,retrolental fibroplasia, neovascular glaucoma, age-related maculardegeneration, diabetic macular edema, corneal neovascularization,corneal graft neovascularization, corneal graft rejection,retinal/choroidal neovascularization, neovascularization of the angle(rubeosis), ocular neovascular disease, vascular restenosis,arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma,thyroid hyperplasias (including Grave's disease), corneal and othertissue transplantation, chronic inflammation, lung inflammation, acutelung injury/ARDS, sepsis, primary pulmonary hypertension, malignantpulmonary effusions, cerebral edema (e.g., associated with acutestroke/closed head injury/trauma), synovial inflammation, pannusformation in RA, myositis ossificans, hypertropic bone formation,osteoarthritis (OA), refractory ascites, polycystic ovarian disease,endometriosis, 3rd spacing of fluid diseases (pancreatitis, compartmentsyndrome, burns, bowel disease), uterine fibroids, premature labor,chronic inflammation such as IBD (Crohn's disease and ulcerativecolitis), renal allograft rejection, inflammatory bowel disease,nephrotic syndrome, undesired or aberrant tissue mass growth(non-cancer), hemophilic joints, hypertrophic scars, inhibition of hairgrowth, Osler-Weber syndrome, pyogenic granuloma retrolentalfibroplasias, scleroderma, trachoma, vascular adhesions, synovitis,dermatitis, preeclampsia, ascites, pericardial effusion (such as thatassociated with pericarditis), and pleural effusion.

The term “Recombinant cell” or “recombinant host cell” herein in generalrefers to any cell engineered to express one or more antibodypolypeptides according to the invention. This includes by way of examplebacterial, fungal, yeast, mammalian, invertebrate such as insect, plantand avian cells. Preferred host cells are yeast, fungi, especiallyfilamentous fungi and mammalian cells. Yeast and filamentous fungiinclude, but are not limited to Pichia pastoris, Pichia finlandica,Pichia trehalophila, Pichia koclamae, Pichia membranaefaciens, Pichiaminuta (Ogataea minuta, Pichia lindneri), Pichia opuntiae, Pichiathermotolerans, Pichia salictaria, Pichia guercuum, Pichia pijperi,Pichia stiptis, Pichia methanolica, Pichia sp., Saccharomycescerevisiae, Saccharomyces sp., Hansenula polymorpha, Kluyveromyces sp.,Kluyveromyces lactis, Candida albicans, Aspergillus nidulans,Aspergillus niger, Aspergillus oryzae, Trichoderma reesei, Chrysosporiumlucknowense, Fusarium sp., Fusarium gramineum, Fusarium venenatum,Physcomitrella patens and Neurospora crassa. Pichia sp., anySaccharomyces sp., Hansenula polymorpha, any Kluyveromyces sp., Candidaalbicans, any Aspergillus sp., Trichoderma reesei, Chrysosporiumlucknowense, any Fusarium sp. and Neurospora crassa.

Examples of invertebrate cells include insect cells such as DrosophilaS2 and Spodoptera Sf9, as well as plant cells. Examples of usefulmammalian host cell lines include Chinese hamster ovary (CHO) and COScells. More specific examples include monkey kidney CV1 line transformedby SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293cells subcloned for growth in suspension culture, Graham et al., J. GenVirol., 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlauband Chasin, Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); mouse sertolicells (TM4, Mather, Biol. Reprod., 23:243-251 (1980)); human lung cells(W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); and mousemammary tumor (MMT 060562, ATCC CCL51). The selection of the appropriatehost cell is deemed to be within the skill in the art. Preferredmammalian cells for antibody expression include CHO cells and COS cells.In an exemplary embodiment the recombinant host cells are haploidal orpolyploidal yeast cells of the genus Pichia.

Mating Competent Yeast Species:

In the present invention this is intended to broadly encompass anydiploid or tetraploid yeast which can be grown in culture. Such speciesof yeast may exist in a haploid, diploid, or other polyploid form. Thecells of a given ploidy may, under appropriate conditions, proliferatefor an indefinite number of generations in that form. Diploid cells canalso sporulate to form haploid cells. Sequential mating can result intetraploid strains through further mating or fusion of diploid strains.The present invention contemplates the use of haploid yeast, as well asdiploid or other polyploid yeast cells produced, for example, by matingor spheroplast fusion.

Mating competent yeast include yeast which are a member of theSaccharomycetaceae family, which includes the genera Arxiozyma;Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera; Eremothecium;Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea; Lodderomyces;Pachysolen; Pichia; Saccharomyces; Saturnispora; Tetrapisispora;Torulaspora; Williopsis; and Zygosaccharomyces. Other types of yeastpotentially useful in the invention include Yarrowia; Rhodosporidium;Candida; Hansenula; Filobasium; Sporidiobolus; Bullera; Leucosporidiumand Filobasidella.

In a preferred embodiment of the invention, the mating competent yeastis a member of the genus Pichia. In a further preferred embodiment ofthe invention, the mating competent yeast of the genus Pichia is one ofthe following species: Pichia pastoris, Pichia methanolica, andHansenula polymorphs (Pichia angusta). In a particularly preferredembodiment of the invention, the mating competent yeast of the genusPichia is the species Pichia pastoris.

Haploid Yeast Cell:

A cell having a single copy of each gene of its normal genomic(chromosomal) complement.

Polyploid Yeast Cell:

A cell having more than one copy of its normal genomic (chromosomal)complement.

Diploid Yeast Cell:

A cell having two copies (alleles) of essentially every gene of itsnormal genomic complement, typically formed by the process of fusion(mating) of two haploid cells.

Tetraploid Yeast Cell:

A cell having four copies (alleles) of essentially every gene of itsnormal genomic complement, typically formed by the process of fusion(mating) of two haploid cells. Tetraploids may carry two, three, four ormore different expression cassettes. Such tetraploids might be obtainedin S. cerevisiae by selective mating homozygotic heterothallic a/a andalpha/alpha diploids and in Pichia by sequential mating of haploids toobtain auxotrophic diploids. For example, a [met his] haploid can bemated with [ade his] haploid to obtain diploid [his]; and a [met arg]haploid can be mated with [ade arg] haploid to obtain diploid [arg];then the diploid [his]×diploid [arg] to obtain a tetraploid prototroph.It will be understood by those of skill in the art that reference to thebenefits and uses of diploid cells may also apply to tetraploid cells.

Yeast Mating:

The process by which two haploid yeast cells naturally fuse to form onediploid yeast cell.

Meiosis:

The process by which a diploid yeast cell undergoes reductive divisionto form four haploid spore products. Each spore may then germinate andform a haploid vegetatively growing cell line.

Selectable Marker:

A selectable marker is a gene or gene fragment that confers a growthphenotype (physical growth characteristic) on a cell receiving that geneas, for example through a transformation event. The selectable markerallows that cell to survive and grow in a selective growth medium underconditions in which cells that do not receive that selectable markergene cannot grow. Selectable marker genes generally fall into severaltypes, including positive selectable marker genes such as a gene thatconfers on a cell resistance to an antibiotic or other drug, temperaturewhen two temperature sensitive (“ts”) mutants are crossed or a is mutantis transformed; negative selectable marker genes such as a biosyntheticgene that confers on a cell the ability to grow in a medium without aspecific nutrient needed by all cells that do not have that biosyntheticgene, or a mutagenized biosynthetic gene that confers on a cellinability to grow by cells that do not have the wild type gene; and thelike. Suitable markers include but are not limited to: ZEO; G418; LYS3;MET1; MET3a; ADE1; ADE3; URA3; and the like.

Expression Vector:

These DNA vectors contain elements that facilitate manipulation for theexpression of a foreign protein within the target host cell.Conveniently, manipulation of sequences and production of DNA fortransformation is first performed in a bacterial host, e.g. E. coli, andusually vectors will include sequences to facilitate such manipulations,including a bacterial origin of replication and appropriate bacterialselection marker. Selection markers encode proteins necessary for thesurvival or growth of transformed host cells grown in a selectiveculture medium. Host cells not transformed with the vector containingthe selection gene will not survive in the culture medium. Typicalselection genes encode proteins that (a) confer resistance toantibiotics or other toxins, (b) complement auxotrophic deficiencies, or(c) supply critical nutrients not available from complex media.Exemplary vectors and methods for transformation of yeast are described,for example, in Burke, D., Dawson, D., & Stearns, T. (2000). Methods inyeast genetics: a Cold Spring Harbor Laboratory course manual.Plainview, N.Y.: Cold Spring Harbor Laboratory Press.

Expression vectors for use in the methods of the invention will furtherinclude a selectable auxotrophic or drug marker for identifyingtransformed cells such as yeast strains. A drug marker may further beused to amplify copy number of the vector in a host cell.

The polypeptide coding sequence of interest is operably linked totranscriptional and translational regulatory sequences that provide forexpression of the polypeptide in yeast cells. These vector componentsmay include, but are not limited to, one or more of the following: anenhancer element, a promoter, and a transcription termination sequence.Sequences for the secretion of the polypeptide may also be included,e.g. a signal sequence, and the like. An origin of replication isoptional, as expression vectors are often integrated into the host,e.g., yeast genome. In one embodiment of the invention, the polypeptideof interest is operably linked, or fused, to sequences providing foroptimized secretion of the polypeptide from yeast diploid cells.

Nucleic acids are “operably linked” when placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for asignal sequence is operably linked to DNA for a polypeptide if it isexpressed as a preprotein that participates in the secretion of thepolypeptide; a promoter or enhancer is operably linked to a codingsequence if it affects the transcription of the sequence. Generally,“operably linked” means that the DNA sequences being linked arecontiguous, and, in the case of a secretory leader, contiguous and inreading frame. However, enhancers do not have to be contiguous. Linkingis accomplished by ligation at convenient restriction sites oralternatively via a PCR/recombination method familiar to those skilledin the art (Gateway® Technology; Invitrogen, Carlsbad Calif.). If suchsites do not exist, the synthetic oligonucleotide adapters or linkersare used in accordance with conventional practice.

Promoters are untranslated sequences located upstream (5′) to the startcodon of a structural gene (generally within about 100 to 1000 bp) thatcontrol the transcription and translation of particular nucleic acidsequences to which they are operably linked. Such promoters fall intoseveral classes: inducible, constitutive, and repressible promoters(that increase levels of transcription in response to absence of arepressor). Inducible promoters may initiate increased levels oftranscription from DNA under their control in response to some change inculture conditions, e.g., the presence or absence of a nutrient or achange in temperature.

The promoter fragment may also serve as the site for homologousrecombination and integration of the expression vector into the samesite in the host genome; alternatively a selectable marker is used asthe site for homologous recombination.

Examples of suitable promoters useful in Pichia include the AOX1 andpromoter (Cregg et al. (1989) Mol. Cell. Biol. 9:1316-1323); ICL1promoter (Menendez et al. (2003) Yeast 20(13): 1097-108);glyceraldehyde-3-phosphate dehydrogenase promoter (GAP) (Waterham et al.(1997) Gene 186(1):37-44); and FLD1 promoter (Shen et al. (1998) Gene216(1):93-102). The GAP promoter is a strong constitutive promoter andthe AOX and FLD1 promoters are inducible.

Other yeast promoters include ADH1, alcohol dehydrogenase II, GAL4,PHO3, PHO5, Pyk, and chimeric promoters derived therefrom. Additionally,non-yeast promoters may be used in the invention such as mammalian,insect, plant, reptile, amphibian, bacterial, fungal, viral, and avianpromoters. Most typically the promoter will comprise a mammalianpromoter (potentially endogenous to the expressed genes) or willcomprise a yeast or viral promoter that provides for efficienttranscription in yeast systems.

The polypeptides of interest may be produced recombinantly not onlydirectly, but also as a fusion polypeptide with a heterologouspolypeptide, e.g. a signal sequence or other polypeptide having aspecific cleavage site at the N-terminus of the mature protein orpolypeptide. In general, the signal sequence may be a component of thevector, or it may be a part of the polypeptide coding sequence that isinserted into the vector. The heterologous signal sequence selectedpreferably is one that is recognized and processed through one of thestandard pathways available within the host cell. The S. cerevisiaealpha factor pre-pro signal has proven effective in the secretion of avariety of recombinant proteins from P. pastoris. Other yeast signalsequences include the alpha mating factor signal sequence, the invertasesignal sequence, and signal sequences derived from other secreted yeastpolypeptides. Additionally, these signal peptide sequences may beengineered to provide for enhanced secretion in diploid yeast expressionsystems. Other secretion signals of interest also include mammaliansignal sequences, which may be heterologous to the protein beingsecreted, or may be a native sequence for the protein being secreted.Signal sequences include pre-peptide sequences, and in some instancesmay include propeptide sequences. Many such signal sequences are knownin the art, including the signal sequences found on immunoglobulinchains, e.g., K28 preprotoxin sequence, PHA-E, FACE, human MCP-1, humanserum albumin signal sequences, human Ig heavy chain, human Ig lightchain, and the like. For example, see Hashimoto et. al. Protein Eng11(2) 75 (1998); and Kobayashi et. al. Therapeutic Apheresis 2(4) 257(1998).

Transcription may be increased by inserting a transcriptional activatorsequence into the vector. These activators are cis-acting elements ofDNA, usually about from 10 to 300 bp, which act on a promoter toincrease its transcription. Transcriptional enhancers are relativelyorientation and position independent, having been found 5′ and 3′ to thetranscription unit, within an intron, as well as within the codingsequence itself. The enhancer may be spliced into the expression vectorat a position 5′ or 3′ to the coding sequence, but is preferably locatedat a site 5′ from the promoter.

Expression vectors used in eukaryotic host cells may also containsequences necessary for the termination of transcription and forstabilizing the mRNA. Such sequences are commonly available from 3′ tothe translation termination codon, in untranslated regions of eukaryoticor viral DNAs or cDNAs. These regions contain nucleotide segmentstranscribed as polyadenylated fragments in the untranslated portion ofthe mRNA.

Construction of suitable vectors containing one or more of theabove-listed components employs standard ligation techniques orPCR/recombination methods. Isolated plasmids or DNA fragments arecleaved, tailored, and re-ligated in the form desired to generate theplasmids required or via recombination methods. For analysis to confirmcorrect sequences in plasmids constructed, the ligation mixtures areused to transform host cells, and successful transformants selected byantibiotic resistance (e.g. ampicillin or Zeocin) where appropriate.Plasmids from the transformants are prepared, analyzed by restrictionendonuclease digestion and/or sequenced.

As an alternative to restriction and ligation of fragments,recombination methods based on att sites and recombination enzymes maybe used to insert DNA sequences into a vector. Such methods aredescribed, for example, by Landy (1989) Ann. Rev. Biochem. 58:913-949;and are known to those of skill in the art. Such methods utilizeintermolecular DNA recombination that is mediated by a mixture of lambdaand E. coli-encoded recombination proteins. Recombination occurs betweenspecific attachment (att) sites on the interacting DNA molecules. For adescription of att sites see Weisberg and Landy (1983) Site-SpecificRecombination in Phage Lambda, in Lambda II, Weisberg, ed. (Cold SpringHarbor, N.Y.:Cold Spring Harbor Press), pp. 211-250. The DNA segmentsflanking the recombination sites are switched, such that afterrecombination, the att sites are hybrid sequences comprised of sequencesdonated by each parental vector. The recombination can occur betweenDNAs of any topology.

Att sites may be introduced into a sequence of interest by ligating thesequence of interest into an appropriate vector; generating a PCRproduct containing att B sites through the use of specific primers;generating a cDNA library cloned into an appropriate vector containingatt sites; and the like.

Folding, as used herein, refers to the three-dimensional structure ofpolypeptides and proteins, where interactions between amino acidresidues act to stabilize the structure. While non-covalent interactionsare important in determining structure, usually the proteins of interestwill have intra- and/or intermolecular covalent disulfide bonds formedby two cysteine residues. For naturally occurring proteins andpolypeptides or derivatives and variants thereof, the proper folding istypically the arrangement that results in optimal biological activity,and can conveniently be monitored by assays for activity, e.g. ligandbinding, enzymatic activity, etc.

In some instances, for example where the desired product is of syntheticorigin, assays based on biological activity will be less meaningful. Theproper folding of such molecules may be determined on the basis ofphysical properties, energetic considerations, modeling studies, and thelike.

The expression host may be further modified by the introduction ofsequences encoding one or more enzymes that enhance folding anddisulfide bond formation, i.e. foldases, chaperonins, etc. Suchsequences may be constitutively or inducibly expressed in the yeast hostcell, using vectors, markers, etc. as known in the art. Preferably thesequences, including transcriptional regulatory elements sufficient forthe desired pattern of expression, are stably integrated in the yeastgenome through a targeted methodology.

For example, the eukaryotic PDI is not only an efficient catalyst ofprotein cysteine oxidation and disulfide bond isomerization, but alsoexhibits chaperone activity. Co-expression of PDI can facilitate theproduction of active proteins having multiple disulfide bonds. Also ofinterest is the expression of BIP (immunoglobulin heavy chain bindingprotein); cyclophilin; and the like. In one embodiment of the invention,each of the haploid parental strains expresses a distinct foldingenzyme, e.g. one strain may express BIP, and the other strain mayexpress PDI or combinations thereof.

The terms “desired protein” or “desired antibody” are usedinterchangeably and refer generally to a parent antibody or fragmentspecific to a target, i.e., HGF or a chimeric or humanized antibody or abinding portion thereof derived therefrom or one containing the sameCDRs or epitopic specificity as any of the anti-HGF antibodies orfragments described herein. The term “antibody” is intended to includeany polypeptide chain-containing molecular structure with a specificshape that fits to and recognizes an epitope, where one or morenon-covalent binding interactions stabilize the complex between themolecular structure and the epitope. The archetypal antibody molecule isthe immunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA,IgE, IgD, etc., from all sources, e.g. human, rodent, rabbit, cow,sheep, pig, dog, other mammals, chicken, other avians, etc., areconsidered to be “antibodies.” A preferred source for producingantibodies useful as starting material according to the invention israbbits. Numerous antibody coding sequences have been described; andothers may be raised by methods well-known in the art. Examples thereofinclude chimeric antibodies, human antibodies and other non-humanmammalian antibodies, humanized antibodies, single chain antibodies(such as scFvs), camelbodies, nanobodies, IgNAR (single-chain antibodiesderived from sharks), small-modular immunopharmaceuticals (SMIPs), andantibody fragments such as Fabs, Fab′, F(ab′)₂, monovalent antibodyfragments such as MetMab like molecules, IgNars and the like. SeeStreltsov V A, et al., Structure of a shark IgNAR antibody variabledomain and modeling of an early-developmental isotype, Protein Sci. 2005November; 14(11):2901-9. Epub 2005 Sep. 30; Greenberg A S, et al., A newantigen receptor gene family that undergoes rearrangement and extensivesomatic diversification in sharks, Nature. 1995 Mar. 9;374(6518):168-73; Nuttall S D, et al., Isolation of the new antigenreceptor from wobbegong sharks, and use as a scaffold for the display ofprotein loop libraries, Mol Immunol. 2001 August; 38(4):313-26;Hamers-Casterman C, et al., Naturally occurring antibodies devoid oflight chains, Nature. 1993 Jun. 3; 363(6428):446-8; Gill D S, et al.,Biopharmaceutical drug discovery using novel protein scaffolds, CurrOpin Biotechnol. 2006 December; 17(6):653-8. Epub 2006 Oct. 19.

The present invention includes in particular includes monovalentantibody molecules that bind HGF, which are analogous to MetMabmolecules. MetMab is a monovalent antibody specific to Met. (Met is aprotein encoded by the nucleotide sequence set forth in Park et al.,Proc. Natl. Acad. Sci. 84, 7479-(1987), or fragments thereof, as well asrelated polypeptides, which include, but are not limited to, allelicvariants, splice variants, derivative variants, substitution variants,deletion variants, and/or insertion variants, fusion polypeptides, andinterspecies homologs). The MetMab antibody, is a monovalent antibodyknown by different names including OA-5d5 (Genentech) and is also calledOne Armed 5d5, 5d5, MetMab, PRO143966, among others). Antibody OA-5d5,including its structure and properties, and methods for making and usingit, are described in U.S. Publication No. 2007/0092520. In oneembodiment, an anti-HGF antibody according to the invention may comprisea single Fab region linked to an Fc region. In such embodiment, anantibody of the invention may comprise light and heavy chain variabledomains as described herein. In such an embodiment, the antibody ismonovalent and may comprise an intact Fc region. In another suchembodiment, the Fc region may comprise at least one protuberance (knob)and at least one cavity (hole), wherein the presence of the protuberanceand cavity enhances formation of a complex between an Fc polypeptidecomprising the protuberance and an Fc polypeptide comprising the cavity,for example as described in WO 2005/063816. In one embodiment, the Fcregion of an antibody of the invention may comprise a first and a secondFc polypeptide, wherein the first and second polypeptide each comprisesone or more mutations with respect to wild type human Fc. In oneembodiment, a cavity mutation is T366S, L368A and/or Y407V. In anotherembodiment, a protuberance mutation is T366W. In a specific embodiment,a monovalent antibody according to the subject invention may comprise aone-armed antibody synthesized as described in WO2005/063816. In suchembodiment, the one-armed antibody may comprise Fc mutationsconstituting “knobs” and “holes” as described in WO2005/063816. Forexample, a hole mutation can be one or more of T366A, L368A and/or Y407Vin an Fc polypeptide, and a cavity mutation can be T366W. The inventionis also directed to an anti-human HGF monovalent agent that binds withthe same HGF epitope and/or competes with an anti-HGF antibody forbinding to HGF as an antibody or antibody fragment disclosed herein.

For example, antibodies or antigen binding fragments may be produced bygenetic engineering. In this technique, as with other methods,antibody-producing cells are sensitized to the desired antigen orimmunogen. The messenger RNA isolated from antibody producing cells isused as a template to make cDNA using PCR amplification. A library ofvectors, each containing one heavy chain gene and one light chain generetaining the initial antigen specificity, is produced by insertion ofappropriate sections of the amplified immunoglobulin cDNA into theexpression vectors. A combinatorial library is constructed by combiningthe heavy chain gene library with the light chain gene library. Thisresults in a library of clones which co-express a heavy and light chain(resembling the Fab fragment or antigen binding fragment of an antibodymolecule). The vectors that carry these genes are co-transfected into ahost cell. When antibody gene synthesis is induced in the transfectedhost, the heavy and light chain proteins self-assemble to produce activeantibodies that can be detected by screening with the antigen orimmunogen.

Antibody coding sequences of interest include those encoded by nativesequences, as well as nucleic acids that, by virtue of the degeneracy ofthe genetic code, are not identical in sequence to the disclosed nucleicacids, and variants thereof. Variant polypeptides can include amino acid(aa) substitutions, additions or deletions. The amino acid substitutionscan be conservative amino acid substitutions or substitutions toeliminate non-essential amino acids, such as to alter a glycosylationsite, or to minimize misfolding by substitution or deletion of one ormore cysteine residues that are not necessary for function. Variants canbe designed so as to retain or have enhanced biological activity of aparticular region of the protein (e.g., a functional domain, catalyticamino acid residues, etc). Variants also include fragments of thepolypeptides disclosed herein, particularly biologically activefragments and/or fragments corresponding to functional domains.Techniques for in vitro mutagenesis of cloned genes are known. Alsoincluded in the subject invention are polypeptides that have beenmodified using ordinary molecular biological techniques so as to improvetheir resistance to proteolytic degradation or to optimize solubilityproperties or to render them more suitable as a therapeutic agent.

Chimeric antibodies may be made by recombinant means by combining thevariable light and heavy chain regions (V_(L) and V_(H)), obtained fromantibody producing cells of one species with the constant light andheavy chain regions from another. Typically chimeric antibodies utilizerodent or rabbit variable regions and human constant regions, in orderto produce an antibody with predominantly human domains. The productionof such chimeric antibodies is well known in the art, and may beachieved by standard means (as described, e.g., in U.S. Pat. No.5,624,659, incorporated herein by reference in its entirety). It isfurther contemplated that the human constant regions of chimericantibodies of the invention may be selected from IgG1, IgG2, IgG3, andIgG4 constant regions.

Humanized antibodies are engineered to contain even more human-likeimmunoglobulin domains, and incorporate only thecomplementarity-determining regions of the animal-derived antibody. Thisis accomplished by carefully examining the sequence of thehyper-variable loops of the variable regions of the monoclonal antibody,and fitting them to the structure of the human antibody chains. Althoughfacially complex, the process is straightforward in practice. See, e.g.,U.S. Pat. No. 6,187,287, incorporated fully herein by reference.

In addition to entire immunoglobulins (or their recombinantcounterparts), immunoglobulin fragments comprising the epitope bindingsite (e.g., Fab′, F(ab′)₂, Fab, or other fragments) may be synthesized.“Fragment” or minimal immunoglobulins may be designed utilizingrecombinant immunoglobulin techniques. For instance “Fv” immunoglobulinsfor use in the present invention may be produced by synthesizing a fusedvariable light chain region and a variable heavy chain region.Combinations of antibodies are also of interest, e.g. diabodies, whichcomprise two distinct Fv specificities. In another embodiment of theinvention, SMIPs (small molecule immunopharmaceuticals), camelbodies,nanobodies, and IgNAR are encompassed by immunoglobulin fragments.

Immunoglobulins and fragments thereof may be modifiedpost-translationally, e.g. To add effector moieties such as chemicallinkers, detectable moieties, such as fluorescent dyes, enzymes, toxins,substrates, bioluminescent materials, radioactive materials,chemiluminescent moieties and the like, or specific binding moieties,such as streptavidin, avidin, or biotin, and the like may be utilized inthe methods and compositions of the present invention. Examples ofadditional effector molecules are provided infra.

A polynucleotide sequence “corresponds” to a polypeptide sequence iftranslation of the polynucleotide sequence in accordance with thegenetic code yields the polypeptide sequence (i.e., the polynucleotidesequence “encodes” the polypeptide sequence), one polynucleotidesequence “corresponds” to another polynucleotide sequence if the twosequences encode the same polypeptide sequence.

A “heterologous” region or domain of a DNA construct is an identifiablesegment of DNA within a larger DNA molecule that is not found inassociation with the larger molecule in nature. Thus, when theheterologous region encodes a mammalian gene, the gene will usually beflanked by DNA that does not flank the mammalian genomic DNA in thegenome of the source organism. Another example of a heterologous regionis a construct where the coding sequence itself is not found in nature(e.g., a cDNA where the genomic coding sequence contains introns, orsynthetic sequences having codons different than the native gene).Allelic variations or naturally-occurring mutational events do not giverise to a heterologous region of DNA as defined herein.

A “coding sequence” is an in-frame sequence of codons that (in view ofthe genetic code) correspond to or encode a protein or peptide sequence.Two coding sequences correspond to each other if the sequences or theircomplementary sequences encode the same amino acid sequences. A codingsequence in association with appropriate regulatory sequences may betranscribed and translated into a polypeptide. A polyadenylation signaland transcription termination sequence will usually be located 3′ to thecoding sequence. A “promoter sequence” is a DNA regulatory regioncapable of binding RNA polymerase in a cell and initiating transcriptionof a downstream (3′ direction) coding sequence. Promoter sequencestypically contain additional sites for binding of regulatory molecules(e.g., transcription factors) which affect the transcription of thecoding sequence. A coding sequence is “under the control” of thepromoter sequence or “operatively linked” to the promoter when RNApolymerase binds the promoter sequence in a cell and transcribes thecoding sequence into mRNA, which is then in turn translated into theprotein encoded by the coding sequence.

Vectors are used to introduce a foreign substance, such as DNA, RNA orprotein, into an organism or host cell. Typical vectors includerecombinant viruses (for polynucleotides) and liposomes (forpolypeptides). A “DNA vector” is a replicon, such as plasmid, phage orcosmid, to which another polynucleotide segment may be attached so as tobring about the replication of the attached segment. An “expressionvector” is a DNA vector which contains regulatory sequences which willdirect polypeptide synthesis by an appropriate host cell. This usuallymeans a promoter to bind RNA polymerase and initiate transcription ofmRNA, as well as ribosome binding sites and initiation signals to directtranslation of the mRNA into a polypeptide(s). Incorporation of apolynucleotide sequence into an expression vector at the proper site andin correct reading frame, followed by transformation of an appropriatehost cell by the vector, enables the production of a polypeptide encodedby said polynucleotide sequence.

“Amplification” of polynucleotide sequences is the in vitro productionof multiple copies of a particular nucleic acid sequence. The amplifiedsequence is usually in the form of DNA. A variety of techniques forcarrying out such amplification are described in a review article by VanBrunt (1990, Bio/Technol., 8(4):291-294). Polymerase chain reaction orPCR is a prototype of nucleic acid amplification, and use of PCR hereinshould be considered exemplary of other suitable amplificationtechniques.

The general structure of antibodies in vertebrates now is wellunderstood (Edelman, G. M., Ann. N.Y. Acad. Sci., 190: 5 (1971)).Antibodies consist of two identical light polypeptide chains ofmolecular weight approximately 23,000 Daltons (the “light chain”), andtwo identical heavy chains of molecular weight 53,000-70,000 (the “heavychain”). The four chains are joined by disulfide bonds in a “Y”configuration wherein the light chains bracket the heavy chains startingat the mouth of the “Y” configuration. The “branch” portion of the “Y”configuration is designated the F_(ab) region; the stem portion of the“Y” configuration is designated the F_(c) region. The amino acidsequence orientation runs from the N-terminal end at the top of the “Y”configuration to the C-terminal end at the bottom of each chain. TheN-terminal end possesses the variable region having specificity for theantigen that elicited it, and is approximately 100 amino acids inlength, there being slight variations between light and heavy chain andfrom antibody to antibody.

The variable region is linked in each chain to a constant region thatextends the remaining length of the chain and that within a particularclass of antibody does not vary with the specificity of the antibody(i.e., the antigen eliciting it). There are five known major classes ofconstant regions that determine the class of the immunoglobulin molecule(IgG, IgM, IgA, IgD, and IgE corresponding to γ, μ, α, δ, and ε (gamma,mu, alpha, delta, or epsilon) heavy chain constant regions). Theconstant region or class determines subsequent effector function of theantibody, including activation of complement (Kabat, E. A., StructuralConcepts in Immunology and Immunochemistry, 2nd Ed., p. 413-436, Holt,Rinehart, Winston (1976)), and other cellular responses (Andrews, D. W.,et al., Clinical Immunobiology, pp 1-18, W. B. Sanders (1980); Kohl, S.,et al., Immunology, 48: 187 (1983)); while the variable regiondetermines the antigen with which it will react. Light chains areclassified as either κ (kappa) or λ (lambda). Each heavy chain class canbe prepared with either kappa or lambda light chain. The light and heavychains are covalently bonded to each other, and the “tail” portions ofthe two heavy chains are bonded to each other by covalent disulfidelinkages when the immunoglobulins are generated either by hybridomas orby B cells.

The expression “variable region” or “VR” refers to the domains withineach pair of light and heavy chains in an antibody that are involveddirectly in binding the antibody to the antigen. Each heavy chain has atone end a variable domain (V_(H)) followed by a number of constantdomains. Each light chain has a variable domain (V_(L)) at one end and aconstant domain at its other end; the constant domain of the light chainis aligned with the first constant domain of the heavy chain, and thelight chain variable domain is aligned with the variable domain of theheavy chain.

The expressions “complementarity determining region,” “hypervariableregion,” or “CDR” refer to one or more of the hyper-variable orcomplementarity determining regions (CDRs) found in the variable regionsof light or heavy chains of an antibody (See Kabat, E. A. et al.,Sequences of Proteins of Immunological Interest, National Institutes ofHealth, Bethesda, Md., (1987)). These expressions include thehypervariable regions as defined by Kabat et al. (“Sequences of Proteinsof Immunological Interest,” Kabat E., et al., US Dept. of Health andHuman Services, 1983) or the hypervariable loops in 3-dimensionalstructures of antibodies (Chothia and Lesk, J Mol. Biol. 196 901-917(1987)). The CDRs in each chain are held in close proximity by frameworkregions and, with the CDRs from the other chain, contribute to theformation of the antigen binding site. Within the CDRs there are selectamino acids that have been described as the selectivity determiningregions (SDRs) which represent the critical contact residues used by theCDR in the antibody-antigen interaction (Kashmiri, S., Methods, 36:25-34(2005)).

An “epitope” or “binding site” is an area or region on an antigen towhich an antigen-binding peptide (such as an antibody) specificallybinds. A protein epitope may comprise amino acid residues directlyinvolved in the binding (also called immunodominant component of theepitope) and other amino acid residues, which are not directly involvedin the binding, such as amino acid residues which are effectivelyblocked by the specifically antigen binding peptide (in other words, theamino acid residue is within the “footprint” of the specifically antigenbinding peptide). The term epitope herein includes both types of aminoacid binding sites in any particular region of HGF that specificallybinds to an anti-HGF antibody. HGF may comprise a number of differentepitopes, which may include, without limitation, (1) linear peptideantigenic determinants, (2) conformational antigenic determinants whichconsist of one or more non-contiguous amino acids located near eachother in a mature HGF conformation; and (3) post-translational antigenicdeterminants which consist, either in whole or part, of molecularstructures covalently attached to a HGF protein such as carbohydrategroups.

The phrase that a first antibody binds “substantially” or “at leastpartially” the same epitope as a second antibody means that the epitopebinding site for the first antibody comprises at least 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, or more of the amino acid residues on theantigen that constitutes the epitope binding site of the secondantibody. Also, that a first antibody binds substantially or partiallythe same or overlapping epitope as a second antibody means that thefirst and second antibodies compete in binding to the antigen, asdescribed above. Thus, the term “binds to substantially the same epitopeor determinant as” a monoclonal antibody means that an antibody“competes” with the antibody.

The phrase “binds to the same or overlapping epitope or determinant as”an antibody of interest means that an antibody “competes” with saidantibody of interest for at least one, or all residues on HGF to whichsaid antibody of interest specifically binds. The identification of oneor more antibodies that bind(s) to substantially or essentially the sameepitope as the monoclonal antibodies described herein can be readilydetermined using any one of variety of immunological screening assays inwhich antibody competition can be assessed. A number of such assays areroutinely practiced and well known in the art (see, e.g., U.S. Pat. No.5,660,827, issued Aug. 26, 1997, which is specifically incorporatedherein by reference). It will be understood that actually determiningthe epitope to which an antibody described herein binds is not in anyway required to identify an antibody that binds to the same orsubstantially the same or overlapping epitope as the monoclonal antibodydescribed herein.

For example, where the test antibodies to be examined are obtained fromdifferent source animals, or are even of a different Ig isotype, asimple competition assay may be employed in which the control antibodyis mixed with the test antibody and then applied to a sample containingHGF. Protocols based upon ELISAs, radioimmunoassays, Western blotting,and the use of surface plasmon resonance (using an instrument such asthe “BIACORE”) or light interferomentry (using an instrument such as the“Octet”) are suitable for use in such simple competition studies.

In certain embodiments, one would pre-mix the control anti-HGF antibodywith varying amounts of the test antibody (e.g., in ratios of about 1:1,1:2, 1:10 or about 1:100) for a period of time prior to applying to theHGF antigen sample. In other embodiments, the control and varyingamounts of test antibody can simply be added separately and admixedduring exposure to the HGF antigen sample. As long as one candistinguish bound from free antibodies (e.g., by using separation orwashing techniques to eliminate unbound antibodies) and control antibodyfrom the test antibody (e.g., by using species specific or isotypespecific secondary antibodies or by specifically labeling the controlantibody with a detectable label) one will be able to determine if thetest antibody reduces the binding of the control antibody to the HGFantigens, indicating that the test antibody recognizes substantially thesame epitope as the control ant-HGF antibody. The binding of the(labeled) control antibody in the presence of a completely irrelevantantibody (that does not bind HGF) can serve as the control high value.The control low value can be obtained by incubating the labeled controlantibody with the same but unlabeled control antibody, where competitionwould occur and reduce binding of the labeled antibody. In a test assay,a significant reduction in labeled antibody reactivity in the presenceof a test antibody is indicative of a test antibody that recognizessubstantially the same epitope, i.e., one that competes with the labeledcontrol antibody. For example, any test antibody that reduces thebinding of the control antibody to HGF s by at least about 50%, such asat least about 60%, or more preferably at least about 70% (e.g., about65-100%), at any ratio of: test antibody between about 1:1 or 1:10 andabout 1:100 is considered to be an antibody that binds to substantiallythe same or overlapping epitope or determinant as the control antibody.

Preferably, such test antibody will reduce the binding of the controlantibody to HGF antigen preferably at least about 50%, at least about60%, at least about 80% or at least about 90% (e.g., about 95%) of thebinding of 1 the control antibody observed in the absence of the testantibody.

Competition can also or alternatively be assessed by, for example, aflow cytometry test. In such a test, cells bearing HGF can be incubatedfirst with a control antibody that binds HGF, and then with the testantibody labeled with a fluorochrome or biotin. The antibody is said tocompete with control antibody if the binding obtained upon preincubationwith saturating amount of control antibody is about 80%, preferablyabout 50%, about 40% or less (e.g., about 30%) of the binding (asmeasured by mean of fluorescence) obtained by the test antibody withoutpreincubation with control antibody. Alternatively, an antibody is saidto compete with the control antibody if the binding obtained with alabeled control antibody (by a fluorochrome or biotin) on cellspreincubated with saturating amount of test antibody is about 80%,preferably about 50%, about 40%, or less (e.g., about 30%) of thebinding obtained without preincubation with the test antibody.

A simple competition assay in which a test antibody is pre-adsorbed andapplied at saturating concentration to a surface onto which HGF isimmobilized also may be advantageously employed. The surface in thesimple competition assay is preferably a BIACORE chip (or other mediasuitable for surface plasmon resonance analysis). The binding of acontrol antibody that binds HGF to the HGF-coated surface is measured.This binding to the HGF-containing surface of the control antibody aloneis compared with the binding of the control antibody in the presence ofa test antibody. A significant reduction in binding to theHGF-containing surface by the control antibody in the presence of a testantibody indicates that the test antibody recognizes substantially thesame epitope as the control antibody such that the test antibody“competes” with the control antibody. Any test antibody that reduces thebinding of control antibody by at least about 20% or more, at leastabout 40%, at least about 50%, at least about 70%, or more, can beconsidered to be an antibody that binds to substantially the sameepitope or determinant as the control antibody. Preferably, such testantibody will reduce the binding of the control antibody to HGF by atleast about 50% (e.g., at least about 60%, at least about 70%, or more).It will be appreciated that the order of control and test antibodies canbe reversed; i.e. The control antibody can be first bound to the surfaceand then the test antibody is brought into contact with the surfacethereafter in a competition assay. Preferably, the antibody havinghigher affinity for HGF antigen is bound to the HGF-containing surfacefirst, as it will be expected that the decrease in binding seen for thesecond antibody (assuming the antibodies are competing) will be ofgreater magnitude. Further examples of such assays are provided in e.g.,Saunal and Regenmortel, (1995) J. Immunol. Methods 183: 33-41, thedisclosure of which is incorporated herein by reference.

In addition, whether an antibody binds the same or overlappingepitope(s) on HGF as another antibody or the epitope bound by a testantibody may in particular be determined using a western-blot basedassay. In this assay a library of peptides corresponding to the antigenbound by the antibody, herein HGF is made, which correspond tooverlapping portions of the protein, typically 10-25, 10-20 or 10-15amino acids long. These different overlapping amino acid peptidesencompassing the HGF sequence are synthesized and covalently bound to aPepSpots nitrocellulose membrane (JPT Peptide technologies, Berlin,Germany). Blots are then prepared and probed according to themanufacturer's recommendations.

Essentially, the immunoblot assay then detects by fluorimetric meanswhat peptides in the library bind to the test antibody and thereby canidentify what residues on the antigen, i.e., HGF, interact with the testantibody. (See an embodiment of this technique in U.S. Pat. No.7,935,340, incorporated by reference herein).

The expressions “framework region” or “FR” refer to one or more of theframework regions within the variable regions of the light and heavychains of an antibody (See Kabat, E. A. et al., Sequences of Proteins ofImmunological Interest, National Institutes of Health, Bethesda, Md.,(1987)). These expressions include those amino acid sequence regionsinterposed between the CDRs within the variable regions of the light andheavy chains of an antibody.

Anti-HGF Antibodies and Binding Fragments Thereof

Antibody Ab1

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 1) QSVEESGGRLVTPGTPLTLTCTVSGFSLSAYAMSWVRQAPEKGLEWIAVIYVIGATDYASWAKGRFTISRTSTTVDLRIPSPTTEDTATYFCARVYDSVWNHFNLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 2) QSVEESGGRLVTPGTPLTLTCTVSGFSLSAYAMSWVRQAPEKGLEWIAVIYVIGATDYASWAKGRFTISRTSTTVDLRIPSPTTEDTATYFCARVYDSVW NHFNLWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab1 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 10) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 21) AYDMTQTPASVEVAVGGTVTIKCQASQSISSWLAWYQQKPGQPPKLLIYQASKLASGVPSRFKGSGSGTEFTLTISGVECADAATYYCQQAYSVSNVDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 22) AYDMTQTPASVEVAVGGTVTIKCQASQSISSWLAWYQQKPGQPPKLLIYQASKLASGVPSRFKGSGSGTEFTLTISGVECADAATYYCQQAYSVSNVDNA FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab1 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 30) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 4; SEQ ID NO: 6; andSEQ ID NO: 8 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the heavy chain sequence of SEQ IDNO: 1 or which contain the variable heavy chain sequence of SEQ ID NO:2, and/or which further contain one, two, or three of the polypeptidesequences of SEQ ID NO: 24; SEQ ID NO: 26; and SEQ ID NO: 28 whichcorrespond to the complementarity-determining regions (CDRs, orhypervariable regions) of the light chain sequence of SEQ ID NO: 21 orwhich contain the variable light chain sequence of SEQ ID NO: 22, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 7; and SEQ ID NO: 9which correspond to the framework regions (FRs or constant regions) ofthe heavy chain sequence of SEQ ID NO: 1 or the variable heavy chainsequence of SEQ ID NO: 2, and/or one, two, three, or four of thepolypeptide sequences of SEQ ID NO: 23; SEQ ID NO: 25; SEQ ID NO: 27;and SEQ ID NO: 29 which correspond to the framework regions (FRs orconstant regions) of the light chain sequence of SEQ ID NO: 21 or thevariable light chain sequence of SEQ ID NO: 22, or combinations of thesepolypeptide sequences or sequences which are at least 80%, 90% or 95%identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 1 or SEQ ID NO: 2 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 21 orSEQ ID NO: 22 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 4; SEQ ID NO: 6; and SEQ ID NO: 8 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 1 or the variable heavy chainsequence of SEQ ID NO: 2 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 24; SEQ ID NO: 26; and SEQ ID NO: 28 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 21 or the variable light chainsequence of SEQ ID NO: 22 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 7; and SEQ ID NO: 9 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 1 or the variable heavy chainsequence of SEQ ID NO: 2 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 23; SEQ ID NO: 25; SEQ ID NO: 27; and SEQ ID NO:29 which correspond to the framework regions (FRs or constant regions)of the light chain sequence of SEQ ID NO: 21 or the variable light chainsequence of SEQ ID NO: 22 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 2; the variable light chain region of SEQ IDNO: 22; the complementarity-determining regions (SEQ ID NO: 4; SEQ IDNO: 6; and SEQ ID NO: 8) of the variable heavy chain region of SEQ IDNO: 2; and the complementarity-determining regions (SEQ ID NO: 24; SEQID NO: 26; and SEQ ID NO: 28) of the variable light chain region of SEQID NO: 22 or sequences that are at least 90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 2; the variable light chain region of SEQ IDNO: 22; the framework regions (SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 7;and SEQ ID NO: 9) of the variable heavy chain region of SEQ ID NO: 2;and the framework regions (SEQ ID NO: 23; SEQ ID NO: 25; SEQ ID NO: 27;and SEQ ID NO: 29) of the variable light chain region of SEQ ID NO: 22.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab1, comprising, or alternatively consisting of, SEQ ID NO:1 and SEQ ID NO: 21, or an antibody or antibody fragment comprising theCDRs of Ab1 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab1 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab1 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab1.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab1, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 2 and the variable lightchain sequence of SEQ ID NO: 22 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 2and/or SEQ ID NO: 22 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab1.In another embodiment of the invention, anti-HGF antibodies such as Ab1or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab1 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab2

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 41) EVQLVESGGGLVQPGGSLRLSCAASGFTVSAYAMSWVRQAPGKGLEWVAVIYVIGATDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYDSVWNHFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 42) EVQLVESGGGLVQPGGSLRLSCAASGFTVSAYAMSWVRQAPGKGLEWVAVIYVIGATDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYD SVWNHFNLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab2 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 50) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 61) DIQMTQSPSTLSASVGDRVTITCQASQSISSWLAWYQQKPGKAPKLLIYQASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVSNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 62) DIQMTQSPSTLSASVGDRVTITCQASQSISSWLAWYQQKPGKAPKLLIYQASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVSNVDNA FGGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab2 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 70) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 44; SEQ ID NO: 46; andSEQ ID NO: 48 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 41 or which contain the variable heavy chain sequence of SEQID NO: 42, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 64; SEQ ID NO: 66; and SEQ ID NO: 68which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the light chain sequence of SEQ ID NO: 61 orwhich contain the variable light chain sequence of SEQ ID NO: 62, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 43; SEQ ID NO: 45; SEQ ID NO: 47; and SEQ ID NO:49 which correspond to the framework regions (FRs or constant regions)of the heavy chain sequence of SEQ ID NO: 41 or the variable heavy chainsequence of SEQ ID NO: 42, and/or one, two, three, or four of thepolypeptide sequences of SEQ ID NO: 63; SEQ ID NO: 65; SEQ ID NO: 67;and SEQ ID NO: 69 which correspond to the framework regions (FRs orconstant regions) of the light chain sequence of SEQ ID NO: 61 or thevariable light chain sequence of SEQ ID NO: 62, or combinations of thesepolypeptide sequences or sequences which are at least 80%, 90% or 95%identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 41 or SEQ ID NO: 42 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 61 orSEQ ID NO: 62 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 44; SEQ ID NO: 46; and SEQ ID NO: 48 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 41 or the variable heavy chainsequence of SEQ ID NO: 42 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 64; SEQ ID NO: 66; and SEQ ID NO: 68 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 61 or the variable light chainsequence of SEQ ID NO: 62 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 43; SEQ ID NO: 45; SEQ ID NO: 47; and SEQ ID NO: 49 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 41 or the variable heavy chainsequence of SEQ ID NO: 42 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 63; SEQ ID NO: 65; SEQ ID NO: 67; and SEQ ID NO:69 which correspond to the framework regions (FRs or constant regions)of the light chain sequence of SEQ ID NO: 61 or the variable light chainsequence of SEQ ID NO: 62 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 42; the variable light chain region of SEQ IDNO: 62; the complementarity-determining regions (SEQ ID NO: 44; SEQ IDNO: 46; and SEQ ID NO: 48) of the variable heavy chain region of SEQ IDNO: 42; and the complementarity-determining regions (SEQ ID NO: 64; SEQID NO: 66; and SEQ ID NO: 68) of the variable light chain region of SEQID NO: 62 or sequences that are at least 90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 42; the variable light chain region of SEQ IDNO: 62; the framework regions (SEQ ID NO: 43; SEQ ID NO: 45; SEQ ID NO:47; and SEQ ID NO: 49) of the variable heavy chain region of SEQ ID NO:42; and the framework regions (SEQ ID NO: 63; SEQ ID NO: 65; SEQ ID NO:67; and SEQ ID NO: 69) of the variable light chain region of SEQ ID NO:62.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab2, comprising, or alternatively consisting of, SEQ ID NO:41 and SEQ ID NO: 61, or an antibody or antibody fragment comprising theCDRs of Ab2 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab2 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab2 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab2.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab2, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 42 and the variable lightchain sequence of SEQ ID NO: 62 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 42and/or SEQ ID NO: 62 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab2.In another embodiment of the invention, anti-HGF antibodies such as Ab2or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab2 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab3

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 81) QSVEESGGRLVTPGTPLTLTCTVSGLTISSYYMSWVRQAPGKGLEWIGTINPGANTYFASWAKGRFTISRTSTTVDLKITSPTTEDTATYFCAREGDSNDWGVFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 82) QSVEESGGRLVTPGTPLTLTCTVSGLTISSYYMSWVRQAPGKGLEWIGTINPGANTYFASWAKGRFTISRTSTTVDLKITSPTTEDTATYFCAREGDSND WGVFDLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab3 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 90) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 101) AYDMTQTPASVEIAVGGTVTIRCQASEDIESYLAWYQQKPGQPPKLLIYRASDLASGVSSRFKGSGSGTDYTLTISGVECDDAATYYCQQGYTIDNVDNTFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 102) AYDMTQTPASVEIAVGGTVTIRCQASEDIESYLAWYQQKPGQPPKLLIYRASDLASGVSSRFKGSGSGTDYTLTISGVECDDAATYYCQQGYTIDNVDNT FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab3 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 110) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 84; SEQ ID NO: 86; andSEQ ID NO: 88 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 81 or which contain the variable heavy chain sequence of SEQID NO: 82, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 104; SEQ ID NO: 106; and SEQ ID NO:108 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 101or which contain the variable light chain sequence of SEQ ID NO: 102, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 83; SEQ ID NO: 85; SEQ ID NO: 87; and SEQ ID NO:89 which correspond to the framework regions (FRs or constant regions)of the heavy chain sequence of SEQ ID NO: 81 or the variable heavy chainsequence of SEQ ID NO: 82, and/or one, two, three, or four of thepolypeptide sequences of SEQ ID NO: 103; SEQ ID NO: 105; SEQ ID NO: 107;and SEQ ID NO: 109 which correspond to the framework regions (FRs orconstant regions) of the light chain sequence of SEQ ID NO: 101 or thevariable light chain sequence of SEQ ID NO: 102, or combinations ofthese polypeptide sequences or sequences which are at least 80%, 90% or95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 81 or SEQ ID NO: 82 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 101 orSEQ ID NO: 102 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 84; SEQ ID NO: 86; and SEQ ID NO: 88 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 81 or the variable heavy chainsequence of SEQ ID NO: 82 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 104; SEQ ID NO: 106; and SEQ ID NO: 108 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 101 or the variable light chainsequence of SEQ ID NO: 102 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 83; SEQ ID NO: 85; SEQ ID NO: 87; and SEQ ID NO: 89 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 81 or the variable heavy chainsequence of SEQ ID NO: 82 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 103; SEQ ID NO: 105; SEQ ID NO: 107; and SEQ IDNO: 109 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 101 or the variablelight chain sequence of SEQ ID NO: 102 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 82; the variable light chain region of SEQ IDNO: 102; the complementarity-determining regions (SEQ ID NO: 84; SEQ IDNO: 86; and SEQ ID NO: 88) of the variable heavy chain region of SEQ IDNO: 82; and the complementarity-determining regions (SEQ ID NO: 104; SEQID NO: 106; and SEQ ID NO: 108) of the variable light chain region ofSEQ ID NO: 102 or sequences that are at least 90% or 95% identicalthereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 82; the variable light chain region of SEQ IDNO: 102; the framework regions (SEQ ID NO: 83; SEQ ID NO: 85; SEQ ID NO:87; and SEQ ID NO: 89) of the variable heavy chain region of SEQ ID NO:82; and the framework regions (SEQ ID NO: 103; SEQ ID NO: 105; SEQ IDNO: 107; and SEQ ID NO: 109) of the variable light chain region of SEQID NO: 102.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab3, comprising, or alternatively consisting of, SEQ ID NO:81 and SEQ ID NO: 101, or an antibody or antibody fragment comprisingthe CDRs of Ab3 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab3 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab3 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab3.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab3, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 82 and the variable lightchain sequence of SEQ ID NO: 102 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 82and/or SEQ ID NO: 102 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab3.In another embodiment of the invention, anti-HGF antibodies such as Ab3or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab3 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab4

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 121) QSLEESGGRLVQPGTPLTLSCTASGLTISSYYMSWVRQAPGKGLEWVGTINPGANTYFASSAKGRFTISRSSTTLDLKMTSPTAEDTATYYCAREGDSNDWGVFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 122) QSLEESGGRLVQPGTPLTLSCTASGLTISSYYMSWVRQAPGKGLEWVGTINPGANTYFASSAKGRFTISRSSTTLDLKMTSPTAEDTATYYCAREGDSND WGVFDLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab4 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 130) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 141) AYDMTQSPASVEAAVGGTVTIRCQASEDIESYLAWYQQKPGQPPKLLIYRASDLASGVSSRFKGSGSGTDYTLTISGLEPEDAATYYCQQGYTIDNVDNTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 142) AYDMTQSPASVEAAVGGTVTIRCQASEDIESYLAWYQQKPGQPPKLLIYRASDLASGVSSRFKGSGSGTDYTLTISGLEPEDAATYYCQQGYTIDNVDNT FGGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab4 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 150) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 124; SEQ ID NO: 126;and SEQ ID NO: 128 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 121 or which contain the variable heavy chain sequence of SEQID NO: 122, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 144; SEQ ID NO: 146; and SEQ ID NO:148 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 141or which contain the variable light chain sequence of SEQ ID NO: 142, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 123; SEQ ID NO: 125; SEQ ID NO: 127; and SEQ IDNO: 129 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 121 or the variableheavy chain sequence of SEQ ID NO: 122, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 143; SEQ ID NO: 145; SEQ IDNO: 147; and SEQ ID NO: 149 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 141or the variable light chain sequence of SEQ ID NO: 142, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 121 or SEQ ID NO: 122 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 141 orSEQ ID NO: 142 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 124; SEQ ID NO: 126; and SEQ ID NO: 128 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 121 or the variable heavy chainsequence of SEQ ID NO: 122 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 144; SEQ ID NO: 146; and SEQ ID NO: 148 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 141 or the variable light chainsequence of SEQ ID NO: 142 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 123; SEQ ID NO: 125; SEQ ID NO: 127; and SEQ ID NO: 129 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 121 or the variable heavy chainsequence of SEQ ID NO: 122 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 143; SEQ ID NO: 145; SEQ ID NO: 147; and SEQ IDNO: 149 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 141 or the variablelight chain sequence of SEQ ID NO: 142 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 122; the variable light chain region of SEQID NO: 142; the complementarity-determining regions (SEQ ID NO: 124; SEQID NO: 126; and SEQ ID NO: 128) of the variable heavy chain region ofSEQ ID NO: 122; and the complementarity-determining regions (SEQ ID NO:144; SEQ ID NO: 146; and SEQ ID NO: 148) of the variable light chainregion of SEQ ID NO: 142 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 122; the variable light chain region of SEQID NO: 142; the framework regions (SEQ ID NO: 123; SEQ ID NO: 125; SEQID NO: 127; and SEQ ID NO: 129) of the variable heavy chain region ofSEQ ID NO: 122; and the framework regions (SEQ ID NO: 143; SEQ ID NO:145; SEQ ID NO: 147; and SEQ ID NO: 149) of the variable light chainregion of SEQ ID NO: 142.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab4, comprising, or alternatively consisting of, SEQ ID NO:121 and SEQ ID NO: 141, or an antibody or antibody fragment comprisingthe CDRs of Ab4 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab4 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab4 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab4.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab4, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 122 and the variable lightchain sequence of SEQ ID NO: 142 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 122and/or SEQ ID NO: 142 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab4.In another embodiment of the invention, anti-HGF antibodies such as Ab4or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab4 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab5

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 161) QSLEESGGRLVTPGTPLTLTCTVSGFSLNNYAVGWVRQAPGKGLEWIGIIYLSGNTDYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARKFDTGYDIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 162) QSLEESGGRLVTPGTPLTLTCTVSGFSLNNYAVGWVRQAPGKGLEWIGIIYLSGNTDYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARKFDTGY DIWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab5 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 170) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 181) AYDMTQTPASMEVAVGGTVTIKCQASQSISTYLAWYQQKPGQPPKLLIYDASDLASGVSSRFKGSGSGTQFTLTISGVECDDAATYYCQQDWSDSNVDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 182) AYDMTQTPASMEVAVGGTVTIKCQASQSISTYLAWYQQKPGQPPKLLIYDASDLASGVSSRFKGSGSGTQFTLTISGVECDDAATYYCQQDWSDSNVDNA FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab5 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 190) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 164; SEQ ID NO: 166;and SEQ ID NO: 168 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 161 or which contain the variable heavy chain sequence of SEQID NO: 162, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 184; SEQ ID NO: 186; and SEQ ID NO:188 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 181or which contain the variable light chain sequence of SEQ ID NO: 182, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 163; SEQ ID NO: 165; SEQ ID NO: 167; and SEQ IDNO: 169 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 161 or the variableheavy chain sequence of SEQ ID NO: 162, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 183; SEQ ID NO: 185; SEQ IDNO: 187; and SEQ ID NO: 189 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 181or the variable light chain sequence of SEQ ID NO: 182, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 161 or SEQ ID NO: 162 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 181 orSEQ ID NO: 182 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 164; SEQ ID NO: 166; and SEQ ID NO: 168 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 161 or the variable heavy chainsequence of SEQ ID NO: 162 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 184; SEQ ID NO: 186; and SEQ ID NO: 188 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 181 or the variable light chainsequence of SEQ ID NO: 182 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 163; SEQ ID NO: 165; SEQ ID NO: 167; and SEQ ID NO: 169 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 161 or the variable heavy chainsequence of SEQ ID NO: 162 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 183; SEQ ID NO: 185; SEQ ID NO: 187; and SEQ IDNO: 189 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 181 or the variablelight chain sequence of SEQ ID NO: 182 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 162; the variable light chain region of SEQID NO: 182; the complementarity-determining regions (SEQ ID NO: 164; SEQID NO: 166; and SEQ ID NO: 168) of the variable heavy chain region ofSEQ ID NO: 162; and the complementarity-determining regions (SEQ ID NO:184; SEQ ID NO: 186; and SEQ ID NO: 188) of the variable light chainregion of SEQ ID NO: 182 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 162; the variable light chain region of SEQID NO: 182; the framework regions (SEQ ID NO: 163; SEQ ID NO: 165; SEQID NO: 167; and SEQ ID NO: 169) of the variable heavy chain region ofSEQ ID NO: 162; and the framework regions (SEQ ID NO: 183; SEQ ID NO:185; SEQ ID NO: 187; and SEQ ID NO: 189) of the variable light chainregion of SEQ ID NO: 182.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab5, comprising, or alternatively consisting of, SEQ ID NO:161 and SEQ ID NO: 181, or an antibody or antibody fragment comprisingthe CDRs of Ab5 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab5 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab5 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab5.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab5, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 162 and the variable lightchain sequence of SEQ ID NO: 182 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 162and/or SEQ ID NO: 182 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab5.In another embodiment of the invention, anti-HGF antibodies such as Ab5or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab5 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab6

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 201) QSVEESGGRLVMPGTPLTLTCTVSGFSLSSNAISWVRQAPEKGLEWIGVIYVIGVTDYASWAQGRFTISKTSTTVDLKIPSPTTEDTATYFCARVYDSGWNHFNLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 202) QSVEESGGRLVMPGTPLTLTCTVSGFSLSSNAISWVRQAPEKGLEWIGVIYVIGVTDYASWAQGRFTISKTSTTVDLKIPSPTTEDTATYFCARVYDSGW NHFNLWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab6 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 210) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 221) ADIVMTQTPSSVEAAVGGTVTIKCQASENIYRLLAWYQQKPGQRPKLLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECADAATYYCQNYYYSSRSSYDTYNVFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 222) ADIVMTQTPSSVEAAVGGTVTIKCQASENIYRLLAWYQQKPGQRPKLLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECADAATYYCQNYYYSSRSSY DTYNVFGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab6 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 230) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206;and SEQ ID NO: 208 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 201 or which contain the variable heavy chain sequence of SEQID NO: 202, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO:228 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 221or which contain the variable light chain sequence of SEQ ID NO: 222, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 203; SEQ ID NO: 205; SEQ ID NO: 207; and SEQ IDNO: 209 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 201 or the variableheavy chain sequence of SEQ ID NO: 202, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 223; SEQ ID NO: 225; SEQ IDNO: 227; and SEQ ID NO: 229 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 221or the variable light chain sequence of SEQ ID NO: 222, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 201 or SEQ ID NO: 202 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 221 orSEQ ID NO: 222 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 204; SEQ ID NO: 206; and SEQ ID NO: 208 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 201 or the variable heavy chainsequence of SEQ ID NO: 202 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 224; SEQ ID NO: 226; and SEQ ID NO: 228 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 221 or the variable light chainsequence of SEQ ID NO: 222 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 203; SEQ ID NO: 205; SEQ ID NO: 207; and SEQ ID NO: 209 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 201 or the variable heavy chainsequence of SEQ ID NO: 202 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 223; SEQ ID NO: 225; SEQ ID NO: 227; and SEQ IDNO: 229 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 221 or the variablelight chain sequence of SEQ ID NO: 222 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 202; the variable light chain region of SEQID NO: 222; the complementarity-determining regions (SEQ ID NO: 204; SEQID NO: 206; and SEQ ID NO: 208) of the variable heavy chain region ofSEQ ID NO: 202; and the complementarity-determining regions (SEQ ID NO:224; SEQ ID NO: 226; and SEQ ID NO: 228) of the variable light chainregion of SEQ ID NO: 222 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 202; the variable light chain region of SEQID NO: 222; the framework regions (SEQ ID NO: 203; SEQ ID NO: 205; SEQID NO: 207; and SEQ ID NO: 209) of the variable heavy chain region ofSEQ ID NO: 202; and the framework regions (SEQ ID NO: 223; SEQ ID NO:225; SEQ ID NO: 227; and SEQ ID NO: 229) of the variable light chainregion of SEQ ID NO: 222.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab6, comprising, or alternatively consisting of, SEQ ID NO:201 and SEQ ID NO: 221, or an antibody or antibody fragment comprisingthe CDRs of Ab6 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab6 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab6 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab6.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab6, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 202 and the variable lightchain sequence of SEQ ID NO: 222 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 202and/or SEQ ID NO: 222 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab6.In another embodiment of the invention, anti-HGF antibodies such as Ab6or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab6 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab7

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 241) QSVEESGGRLVMPGTPLTLTCTVSGFSLSSNAISWVRQAPEKGLEWIGVIYVIGVTDYASWAQGRFTISKTSTTVDLKIPSPTTEDTATYFCARVYDSGWNHFNLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 242) QSVEESGGRLVMPGTPLTLTCTVSGFSLSSNAISWVRQAPEKGLEWIGVIYVIGVTDYASWAQGRFTISKTSTTVDLKIPSPTTEDTATYFCARVYDSGW NHFNLWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab7 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 250) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 261) AYDMTQTPASVEVAVGGTVTIKCQASQSISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTQFTLTISGVECADAATYYCQQAYSVANVDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 262) AYDMTQTPASVEVAVGGTVTIKCQASQSISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTQFTLTISGVECADAATYYCQQAYSVANVDNA FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab7 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 270) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 244; SEQ ID NO: 246;and SEQ ID NO: 248 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 241 or which contain the variable heavy chain sequence of SEQID NO: 242, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 264; SEQ ID NO: 266; and SEQ ID NO:268 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 261or which contain the variable light chain sequence of SEQ ID NO: 262, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 243; SEQ ID NO: 245; SEQ ID NO: 247; and SEQ IDNO: 249 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 241 or the variableheavy chain sequence of SEQ ID NO: 242, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 263; SEQ ID NO: 265; SEQ IDNO: 267; and SEQ ID NO: 269 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 261or the variable light chain sequence of SEQ ID NO: 262, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 241 or SEQ ID NO: 242 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 261 orSEQ ID NO: 262 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 244; SEQ ID NO: 246; and SEQ ID NO: 248 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 241 or the variable heavy chainsequence of SEQ ID NO: 242 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 264; SEQ ID NO: 266; and SEQ ID NO: 268 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 261 or the variable light chainsequence of SEQ ID NO: 262 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 243; SEQ ID NO: 245; SEQ ID NO: 247; and SEQ ID NO: 249 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 241 or the variable heavy chainsequence of SEQ ID NO: 242 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 263; SEQ ID NO: 265; SEQ ID NO: 267; and SEQ IDNO: 269 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 261 or the variablelight chain sequence of SEQ ID NO: 262 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 242; the variable light chain region of SEQID NO: 262; the complementarity-determining regions (SEQ ID NO: 244; SEQID NO: 246; and SEQ ID NO: 248) of the variable heavy chain region ofSEQ ID NO: 242; and the complementarity-determining regions (SEQ ID NO:264; SEQ ID NO: 266; and SEQ ID NO: 268) of the variable light chainregion of SEQ ID NO: 262 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 242; the variable light chain region of SEQID NO: 262; the framework regions (SEQ ID NO: 243; SEQ ID NO: 245; SEQID NO: 247; and SEQ ID NO: 249) of the variable heavy chain region ofSEQ ID NO: 242; and the framework regions (SEQ ID NO: 263; SEQ ID NO:265; SEQ ID NO: 267; and SEQ ID NO: 269) of the variable light chainregion of SEQ ID NO: 262.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab7, comprising, or alternatively consisting of, SEQ ID NO:241 and SEQ ID NO: 261, or an antibody or antibody fragment comprisingthe CDRs of Ab7 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab7 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab7 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab7.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab7, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 242 and the variable lightchain sequence of SEQ ID NO: 262 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 242and/or SEQ ID NO: 262 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab7.In another embodiment of the invention, anti-HGF antibodies such as Ab7or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab7 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab8

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 281) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNAISWVRQAPGKGLEWVGVIYVIGVTDYASSAQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYDSGWNHFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 282) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNAISWVRQAPGKGLEWVGVIYVIGVTDYASSAQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYD SGWNHFNLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab8 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 290) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 301) DIQMTQSPSTLSASVGDRVTITCQASQSISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVANVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 302) DIQMTQSPSTLSASVGDRVTITCQASQSISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVANVDNA FGGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab8 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 310) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 284; SEQ ID NO: 286;and SEQ ID NO: 288 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 281 or which contain the variable heavy chain sequence of SEQID NO: 282, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 304; SEQ ID NO: 306; and SEQ ID NO:308 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 301or which contain the variable light chain sequence of SEQ ID NO: 302, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 283; SEQ ID NO: 285; SEQ ID NO: 287; and SEQ IDNO: 289 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 281 or the variableheavy chain sequence of SEQ ID NO: 282, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 303; SEQ ID NO: 305; SEQ IDNO: 307; and SEQ ID NO: 309 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 301or the variable light chain sequence of SEQ ID NO: 302, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 281 or SEQ ID NO: 282 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 301 orSEQ ID NO: 302 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 284; SEQ ID NO: 286; and SEQ ID NO: 288 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 281 or the variable heavy chainsequence of SEQ ID NO: 282 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 304; SEQ ID NO: 306; and SEQ ID NO: 308 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 301 or the variable light chainsequence of SEQ ID NO: 302 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 283; SEQ ID NO: 285; SEQ ID NO: 287; and SEQ ID NO: 289 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 281 or the variable heavy chainsequence of SEQ ID NO: 282 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 303; SEQ ID NO: 305; SEQ ID NO: 307; and SEQ IDNO: 309 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 301 or the variablelight chain sequence of SEQ ID NO: 302 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 282; the variable light chain region of SEQID NO: 302; the complementarity-determining regions (SEQ ID NO: 284; SEQID NO: 286; and SEQ ID NO: 288) of the variable heavy chain region ofSEQ ID NO: 282; and the complementarity-determining regions (SEQ ID NO:304; SEQ ID NO: 306; and SEQ ID NO: 308) of the variable light chainregion of SEQ ID NO: 302 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 282; the variable light chain region of SEQID NO: 302; the framework regions (SEQ ID NO: 283; SEQ ID NO: 285; SEQID NO: 287; and SEQ ID NO: 289) of the variable heavy chain region ofSEQ ID NO: 282; and the framework regions (SEQ ID NO: 303; SEQ ID NO:305; SEQ ID NO: 307; and SEQ ID NO: 309) of the variable light chainregion of SEQ ID NO: 302.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab8, comprising, or alternatively consisting of, SEQ ID NO:281 and SEQ ID NO: 301, or an antibody or antibody fragment comprisingthe CDRs of Ab8 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab8 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab8 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab8.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab8, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 282 and the variable lightchain sequence of SEQ ID NO: 302 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 282and/or SEQ ID NO: 302 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab8.In another embodiment of the invention, anti-HGF antibodies such as Ab8or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab8 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab9

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 321) QSVEESGGRLVTPGTPLTLTCTVSGIDLNSNGMSWVRQAPGEGLEWIGASSIDGTTYYTNWAKGRFTISKTSSTTVDLKITSPTTEDTATYFCTRGEYAGVVGSNYFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 322) QSVEESGGRLVTPGTPLTLTCTVSGIDLNSNGMSWVRQAPGEGLEWIGASSIDGTTYYTNWAKGRFTISKTSSTTVDLKITSPTTEDTATYFCTRGEYAG VVGSNYFDLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab9 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 330) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 341) QVLTQTPPSVSAVVGGTVTINCQSSQRIYSNWLSWYQQKPGQTPKPLIYAASSLASGVPSRFKGSGSGTQFTLTISDLECDDAASYYCAGYYSGHIYSFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 342) QVLTQTPPSVSAVVGGTVTINCQSSQRIYSNWLSWYQQKPGQTPKPLIYAASSLASGVPSRFKGSGSGTQFTLTISDLECDDAASYYCAGYYSGHIYSFG GGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab9 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 350) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 324; SEQ ID NO: 326;and SEQ ID NO: 328 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 321 or which contain the variable heavy chain sequence of SEQID NO: 322, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 344; SEQ ID NO: 346; and SEQ ID NO:348 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 341or which contain the variable light chain sequence of SEQ ID NO: 342, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 323; SEQ ID NO: 325; SEQ ID NO: 327; and SEQ IDNO: 329 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 321 or the variableheavy chain sequence of SEQ ID NO: 322, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 343; SEQ ID NO: 345; SEQ IDNO: 347; and SEQ ID NO: 349 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 341or the variable light chain sequence of SEQ ID NO: 342, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 321 or SEQ ID NO: 322 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 341 orSEQ ID NO: 342 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 324; SEQ ID NO: 326; and SEQ ID NO: 328 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 321 or the variable heavy chainsequence of SEQ ID NO: 322 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 344; SEQ ID NO: 346; and SEQ ID NO: 348 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 341 or the variable light chainsequence of SEQ ID NO: 342 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 323; SEQ ID NO: 325; SEQ ID NO: 327; and SEQ ID NO: 329 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 321 or the variable heavy chainsequence of SEQ ID NO: 322 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 343; SEQ ID NO: 345; SEQ ID NO: 347; and SEQ IDNO: 349 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 341 or the variablelight chain sequence of SEQ ID NO: 342 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 322; the variable light chain region of SEQID NO: 342; the complementarity-determining regions (SEQ ID NO: 324; SEQID NO: 326; and SEQ ID NO: 328) of the variable heavy chain region ofSEQ ID NO: 322; and the complementarity-determining regions (SEQ ID NO:344; SEQ ID NO: 346; and SEQ ID NO: 348) of the variable light chainregion of SEQ ID NO: 342 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 322; the variable light chain region of SEQID NO: 342; the framework regions (SEQ ID NO: 323; SEQ ID NO: 325; SEQID NO: 327; and SEQ ID NO: 329) of the variable heavy chain region ofSEQ ID NO: 322; and the framework regions (SEQ ID NO: 343; SEQ ID NO:345; SEQ ID NO: 347; and SEQ ID NO: 349) of the variable light chainregion of SEQ ID NO: 342.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab9, comprising, or alternatively consisting of, SEQ ID NO:321 and SEQ ID NO: 341, or an antibody or antibody fragment comprisingthe CDRs of Ab9 and having at least one of the biological activities setforth herein or is an anti-HGF antibody that competes with Ab9 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab9 or an antibody that binds to the same oroverlapping epitope(s) on HGF as Ab9.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab9, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 322 and the variable lightchain sequence of SEQ ID NO: 342 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 322and/or SEQ ID NO: 342 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab9.In another embodiment of the invention, anti-HGF antibodies such as Ab9or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab9 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab10

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 361) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNGMSWVRQAPGKGLEWVGASSIDGTTYYTNSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGEYAGVVGSNYFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 362) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNGMSWVRQAPGKGLEWVGASSIDGTTYYTNSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGEYAGVVGSNYFDLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab10 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 370) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 381) DIQMTQSPSSVSASVGDRVTITCQSSQRIYSNWLSWYQQKPGKAPKLLIYAASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAGYYSGHIYSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 382) DIQMTQSPSSVSASVGDRVTITCQSSQRIYSNWLSWYQQKPGKAPKLLIYAASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAGYYSGHIYSF GGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab10 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 390) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 364; SEQ ID NO: 366;and SEQ ID NO: 368 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 361 or which contain the variable heavy chain sequence of SEQID NO: 362, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 384; SEQ ID NO: 386; and SEQ ID NO:388 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 381or which contain the variable light chain sequence of SEQ ID NO: 382, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 363; SEQ ID NO: 365; SEQ ID NO: 367; and SEQ IDNO: 369 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 361 or the variableheavy chain sequence of SEQ ID NO: 362, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 383; SEQ ID NO: 385; SEQ IDNO: 387; and SEQ ID NO: 389 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 381or the variable light chain sequence of SEQ ID NO: 382, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 361 or SEQ ID NO: 362 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 381 orSEQ ID NO: 382 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 364; SEQ ID NO: 366; and SEQ ID NO: 368 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 361 or the variable heavy chainsequence of SEQ ID NO: 362 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 384; SEQ ID NO: 386; and SEQ ID NO: 388 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 381 or the variable light chainsequence of SEQ ID NO: 382 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 363; SEQ ID NO: 365; SEQ ID NO: 367; and SEQ ID NO: 369 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 361 or the variable heavy chainsequence of SEQ ID NO: 362 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 383; SEQ ID NO: 385; SEQ ID NO: 387; and SEQ IDNO: 389 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 381 or the variablelight chain sequence of SEQ ID NO: 382 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 362; the variable light chain region of SEQID NO: 382; the complementarity-determining regions (SEQ ID NO: 364; SEQID NO: 366; and SEQ ID NO: 368) of the variable heavy chain region ofSEQ ID NO: 362; and the complementarity-determining regions (SEQ ID NO:384; SEQ ID NO: 386; and SEQ ID NO: 388) of the variable light chainregion of SEQ ID NO: 382 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 362; the variable light chain region of SEQID NO: 382; the framework regions (SEQ ID NO: 363; SEQ ID NO: 365; SEQID NO: 367; and SEQ ID NO: 369) of the variable heavy chain region ofSEQ ID NO: 362; and the framework regions (SEQ ID NO: 383; SEQ ID NO:385; SEQ ID NO: 387; and SEQ ID NO: 389) of the variable light chainregion of SEQ ID NO: 382.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab10, comprising, or alternatively consisting of, SEQ ID NO:361 and SEQ ID NO: 381, or an antibody or antibody fragment comprisingthe CDRs of Ab10 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab10 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab10 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab10.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab10, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 362 and the variable lightchain sequence of SEQ ID NO: 382 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 362and/or SEQ ID NO: 382 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab10.In another embodiment of the invention, anti-HGF antibodies such as Ab10or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab10 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab11

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 401) QSMEESGGRLVTPGTPLTLTCTVSGFSLSDYALSWVRQAPGKGLEWIGMISSGDNTYYASWAKGRFTISKASTTVDLKITSPTTEDTATYFCARDKDASSGGYLVLDLLDVPDGMDLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 402) QSMEESGGRLVTPGTPLTLTCTVSGFSLSDYALSWVRQAPGKGLEWIGMISSGDNTYYASWAKGRFTISKASTTVDLKITSPTTEDTATYFCARDKDASSGGYLVLDLLDVPDGMDLWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab11 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 410) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 421) AVLTQTPSPVSAAVGGTVTIKCQSSQSVYNNNLLSWYQQKPGQPPKLLIWGASYLPSGVPDRFSGSGSGTQFTLTISGVQCDDAATYYCLGGYDGDADTYNTFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 422) AVLTQTPSPVSAAVGGTVTIKCQSSQSVYNNNLLSWYQQKPGQPPKLLIWGASYLPSGVPDRFSGSGSGTQFTLTISGVQCDDAATYYCLGGYDGDADTY NTFGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab11 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 430) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 404; SEQ ID NO: 406;and SEQ ID NO: 408 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 401 or which contain the variable heavy chain sequence of SEQID NO: 402, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 424; SEQ ID NO: 426; and SEQ ID NO:428 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 421or which contain the variable light chain sequence of SEQ ID NO: 422, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 403; SEQ ID NO: 405; SEQ ID NO: 407; and SEQ IDNO: 409 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 401 or the variableheavy chain sequence of SEQ ID NO: 402, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 423; SEQ ID NO: 425; SEQ IDNO: 427; and SEQ ID NO: 429 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 421or the variable light chain sequence of SEQ ID NO: 422, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 401 or SEQ ID NO: 402 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 421 orSEQ ID NO: 422 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 404; SEQ ID NO: 406; and SEQ ID NO: 408 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 401 or the variable heavy chainsequence of SEQ ID NO: 402 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 424; SEQ ID NO: 426; and SEQ ID NO: 428 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 421 or the variable light chainsequence of SEQ ID NO: 422 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 403; SEQ ID NO: 405; SEQ ID NO: 407; and SEQ ID NO: 409 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 401 or the variable heavy chainsequence of SEQ ID NO: 402 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 423; SEQ ID NO: 425; SEQ ID NO: 427; and SEQ IDNO: 429 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 421 or the variablelight chain sequence of SEQ ID NO: 422 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 402; the variable light chain region of SEQID NO: 422; the complementarity-determining regions (SEQ ID NO: 404; SEQID NO: 406; and SEQ ID NO: 408) of the variable heavy chain region ofSEQ ID NO: 402; and the complementarity-determining regions (SEQ ID NO:424; SEQ ID NO: 426; and SEQ ID NO: 428) of the variable light chainregion of SEQ ID NO: 422 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 402; the variable light chain region of SEQID NO: 422; the framework regions (SEQ ID NO: 403; SEQ ID NO: 405; SEQID NO: 407; and SEQ ID NO: 409) of the variable heavy chain region ofSEQ ID NO: 402; and the framework regions (SEQ ID NO: 423; SEQ ID NO:425; SEQ ID NO: 427; and SEQ ID NO: 429) of the variable light chainregion of SEQ ID NO: 422.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab11, comprising, or alternatively consisting of, SEQ ID NO:401 and SEQ ID NO: 421, or an antibody or antibody fragment comprisingthe CDRs of Ab11 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab11 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab11 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab11.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab11, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 402 and the variable lightchain sequence of SEQ ID NO: 422 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 402and/or SEQ ID NO: 422 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab11.In another embodiment of the invention, anti-HGF antibodies such as Ab11or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab11 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab12

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 441) QSLEESGGRLVTPGGSLTLTCTVSGIDLSSNAISWVRQAPEKGLEWIAVIYVVGATDYASWAKGRFTISRTSTTVDLKMTSLTTEDTATYFCARVYDSGWNHFNLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 442) QSLEESGGRLVTPGGSLTLTCTVSGIDLSSNAISWVRQAPEKGLEWIAVIYVVGATDYASWAKGRFTISRTSTTVDLKMTSLTTEDTATYFCARVYDSGW NHFNLWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab12 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 450) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 461) AYDMTQTPASVEVAVGGTVTIKCQVSQSISSWLSWYQKKPGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISGVECADAATYYCQQAYSVSNVDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 462) AYDMTQTPASVEVAVGGTVTIKCQVSQSISSWLSWYQKKPGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISGVECADAATYYCQQAYSVSNVDNA FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab12 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 470) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 444; SEQ ID NO: 446;and SEQ ID NO: 448 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 441 or which contain the variable heavy chain sequence of SEQID NO: 442, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 464; SEQ ID NO: 466; and SEQ ID NO:468 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 461or which contain the variable light chain sequence of SEQ ID NO: 462, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 443; SEQ ID NO: 445; SEQ ID NO: 447; and SEQ IDNO: 449 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 441 or the variableheavy chain sequence of SEQ ID NO: 442, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 463; SEQ ID NO: 465; SEQ IDNO: 467; and SEQ ID NO: 469 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 461or the variable light chain sequence of SEQ ID NO: 462, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 441 or SEQ ID NO: 442 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 461 orSEQ ID NO: 462 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 444; SEQ ID NO: 446; and SEQ ID NO: 448 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 441 or the variable heavy chainsequence of SEQ ID NO: 442 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 464; SEQ ID NO: 466; and SEQ ID NO: 468 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 461 or the variable light chainsequence of SEQ ID NO: 462 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 443; SEQ ID NO: 445; SEQ ID NO: 447; and SEQ ID NO: 449 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 441 or the variable heavy chainsequence of SEQ ID NO: 442 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 463; SEQ ID NO: 465; SEQ ID NO: 467; and SEQ IDNO: 469 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 461 or the variablelight chain sequence of SEQ ID NO: 462 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 442; the variable light chain region of SEQID NO: 462; the complementarity-determining regions (SEQ ID NO: 444; SEQID NO: 446; and SEQ ID NO: 448) of the variable heavy chain region ofSEQ ID NO: 442; and the complementarity-determining regions (SEQ ID NO:464; SEQ ID NO: 466; and SEQ ID NO: 468) of the variable light chainregion of SEQ ID NO: 462 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 442; the variable light chain region of SEQID NO: 462; the framework regions (SEQ ID NO: 443; SEQ ID NO: 445; SEQID NO: 447; and SEQ ID NO: 449) of the variable heavy chain region ofSEQ ID NO: 442; and the framework regions (SEQ ID NO: 463; SEQ ID NO:465; SEQ ID NO: 467; and SEQ ID NO: 469) of the variable light chainregion of SEQ ID NO: 462.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab12, comprising, or alternatively consisting of, SEQ ID NO:441 and SEQ ID NO: 461, or an antibody or antibody fragment comprisingthe CDRs of Ab12 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab12 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab12 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab12.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab12, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 442 and the variable lightchain sequence of SEQ ID NO: 462 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 442and/or SEQ ID NO: 462 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab12.In another embodiment of the invention, anti-HGF antibodies such as Ab12or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab12 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab13

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 481) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNAISWVRQAPGKGLEWVAVIYVVGATDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYDSGWNHFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 482) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNAISWVRQAPGKGLEWVAVIYVVGATDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYD SGWNHFNLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab13 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 490) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 501) DYQMTQSPSTLSASVGDRVTITCQVSQSISSWLSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVSNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 502) DYQMTQSPSTLSASVGDRVTITCQVSQSISSWLSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVSNVDNA FGGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab13 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 510) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 484; SEQ ID NO: 486;and SEQ ID NO: 488 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 481 or which contain the variable heavy chain sequence of SEQID NO: 482, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 504; SEQ ID NO: 506; and SEQ ID NO:508 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 501or which contain the variable light chain sequence of SEQ ID NO: 502, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 483; SEQ ID NO: 485; SEQ ID NO: 487; and SEQ IDNO: 489 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 481 or the variableheavy chain sequence of SEQ ID NO: 482, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 503; SEQ ID NO: 505; SEQ IDNO: 507; and SEQ ID NO: 509 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 501or the variable light chain sequence of SEQ ID NO: 502, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 481 or SEQ ID NO: 482 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 501 orSEQ ID NO: 502 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 484; SEQ ID NO: 486; and SEQ ID NO: 488 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 481 or the variable heavy chainsequence of SEQ ID NO: 482 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 504; SEQ ID NO: 506; and SEQ ID NO: 508 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 501 or the variable light chainsequence of SEQ ID NO: 502 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 483; SEQ ID NO: 485; SEQ ID NO: 487; and SEQ ID NO: 489 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 481 or the variable heavy chainsequence of SEQ ID NO: 482 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 503; SEQ ID NO: 505; SEQ ID NO: 507; and SEQ IDNO: 509 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 501 or the variablelight chain sequence of SEQ ID NO: 502 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 482; the variable light chain region of SEQID NO: 502; the complementarity-determining regions (SEQ ID NO: 484; SEQID NO: 486; and SEQ ID NO: 488) of the variable heavy chain region ofSEQ ID NO: 482; and the complementarity-determining regions (SEQ ID NO:504; SEQ ID NO: 506; and SEQ ID NO: 508) of the variable light chainregion of SEQ ID NO: 502 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 482; the variable light chain region of SEQID NO: 502; the framework regions (SEQ ID NO: 483; SEQ ID NO: 485; SEQID NO: 487; and SEQ ID NO: 489) of the variable heavy chain region ofSEQ ID NO: 482; and the framework regions (SEQ ID NO: 503; SEQ ID NO:505; SEQ ID NO: 507; and SEQ ID NO: 509) of the variable light chainregion of SEQ ID NO: 502.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab13, comprising, or alternatively consisting of, SEQ ID NO:481 and SEQ ID NO: 501, or an antibody or antibody fragment comprisingthe CDRs of Ab13 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab13 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab13 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab13.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab13, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 482 and the variable lightchain sequence of SEQ ID NO: 502 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 482and/or SEQ ID NO: 502 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab13.In another embodiment of the invention, anti-HGF antibodies such as Ab13or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab13 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab14

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 521) QSVEESGGRLVTPGTPLTLTCTVSGFSLSNYAMTWVRQAPGKGLEWIGVISFGGNTYYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARWDAENNEILNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 522) QSVEESGGRLVTPGTPLTLTCTVSGFSLSNYAMTWVRQAPGKGLEWIGVISFGGNTYYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARWDAENN EILNLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab14 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 530) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 541) AYDMTQTPASVEVAVGGTVTIKCQASESIESYLAWYQQKSGQPPKLLIYRASTLASGVSSRFKGSGSGTQFTLTISGVECADAATYYCQQGDAWSNVDNVFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 542) AYDMTQTPASVEVAVGGTVTIKCQASESIESYLAWYQQKSGQPPKLLIYRASTLASGVSSRFKGSGSGTQFTLTISGVECADAATYYCQQGDAWSNVDNV FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab14 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 550) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 524; SEQ ID NO: 526;and SEQ ID NO: 528 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 521 or which contain the variable heavy chain sequence of SEQID NO: 522, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 544; SEQ ID NO: 546; and SEQ ID NO:548 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 541or which contain the variable light chain sequence of SEQ ID NO: 542, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 523; SEQ ID NO: 525; SEQ ID NO: 527; and SEQ IDNO: 529 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 521 or the variableheavy chain sequence of SEQ ID NO: 522, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 543; SEQ ID NO: 545; SEQ IDNO: 547; and SEQ ID NO: 549 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 541or the variable light chain sequence of SEQ ID NO: 542, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 521 or SEQ ID NO: 522 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 541 orSEQ ID NO: 542 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 524; SEQ ID NO: 526; and SEQ ID NO: 528 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 521 or the variable heavy chainsequence of SEQ ID NO: 522 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 544; SEQ ID NO: 546; and SEQ ID NO: 548 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 541 or the variable light chainsequence of SEQ ID NO: 542 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 523; SEQ ID NO: 525; SEQ ID NO: 527; and SEQ ID NO: 529 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 521 or the variable heavy chainsequence of SEQ ID NO: 522 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 543; SEQ ID NO: 545; SEQ ID NO: 547; and SEQ IDNO: 549 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 541 or the variablelight chain sequence of SEQ ID NO: 542 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 522; the variable light chain region of SEQID NO: 542; the complementarity-determining regions (SEQ ID NO: 524; SEQID NO: 526; and SEQ ID NO: 528) of the variable heavy chain region ofSEQ ID NO: 522; and the complementarity-determining regions (SEQ ID NO:544; SEQ ID NO: 546; and SEQ ID NO: 548) of the variable light chainregion of SEQ ID NO: 542 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 522; the variable light chain region of SEQID NO: 542; the framework regions (SEQ ID NO: 523; SEQ ID NO: 525; SEQID NO: 527; and SEQ ID NO: 529) of the variable heavy chain region ofSEQ ID NO: 522; and the framework regions (SEQ ID NO: 543; SEQ ID NO:545; SEQ ID NO: 547; and SEQ ID NO: 549) of the variable light chainregion of SEQ ID NO: 542.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab14, comprising, or alternatively consisting of, SEQ ID NO:521 and SEQ ID NO: 541, or an antibody or antibody fragment comprisingthe CDRs of Ab14 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab14 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab14 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab14.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab14, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 522 and the variable lightchain sequence of SEQ ID NO: 542 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 522and/or SEQ ID NO: 542 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab14.In another embodiment of the invention, anti-HGF antibodies such as Ab14or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab14 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab15

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 561) QSVEESGGRLVTPGTPLTLTCTVSGFSLSNYAMTWVRQAPGKGLEWIGVISFGGNTYYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARWDAENNEILNLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 562) QSVEESGGRLVTPGTPLTLTCTVSGFSLSNYAMTWVRQAPGKGLEWIGVISFGGNTYYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARWDAENN EILNLWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab15 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 570) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 581) AYDMTQTPASVEVAVGGTVTIKCQASESISSYLAWYQQKSGQPPKLLIYRASTLASGVSSRFKGSGSGTQFTLTISGVECADAATYYCQQGDAWSNVDNVFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 582) AYDMTQTPASVEVAVGGTVTIKCQASESISSYLAWYQQKSGQPPKLLIYRASTLASGVSSRFKGSGSGTQFTLTISGVECADAATYYCQQGDAWSNVDNV FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab15 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 590) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 564; SEQ ID NO: 566;and SEQ ID NO: 568 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 561 or which contain the variable heavy chain sequence of SEQID NO: 562, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 584; SEQ ID NO: 586; and SEQ ID NO:588 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 581or which contain the variable light chain sequence of SEQ ID NO: 582, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 563; SEQ ID NO: 565; SEQ ID NO: 567; and SEQ IDNO: 569 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 561 or the variableheavy chain sequence of SEQ ID NO: 562, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 583; SEQ ID NO: 585; SEQ IDNO: 587; and SEQ ID NO: 589 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 581or the variable light chain sequence of SEQ ID NO: 582, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 561 or SEQ ID NO: 562 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 581 orSEQ ID NO: 582 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 564; SEQ ID NO: 566; and SEQ ID NO: 568 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 561 or the variable heavy chainsequence of SEQ ID NO: 562 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 584; SEQ ID NO: 586; and SEQ ID NO: 588 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 581 or the variable light chainsequence of SEQ ID NO: 582 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 563; SEQ ID NO: 565; SEQ ID NO: 567; and SEQ ID NO: 569 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 561 or the variable heavy chainsequence of SEQ ID NO: 562 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 583; SEQ ID NO: 585; SEQ ID NO: 587; and SEQ IDNO: 589 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 581 or the variablelight chain sequence of SEQ ID NO: 582 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 562; the variable light chain region of SEQID NO: 582; the complementarity-determining regions (SEQ ID NO: 564; SEQID NO: 566; and SEQ ID NO: 568) of the variable heavy chain region ofSEQ ID NO: 562; and the complementarity-determining regions (SEQ ID NO:584; SEQ ID NO: 586; and SEQ ID NO: 588) of the variable light chainregion of SEQ ID NO: 582 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 562; the variable light chain region of SEQID NO: 582; the framework regions (SEQ ID NO: 563; SEQ ID NO: 565; SEQID NO: 567; and SEQ ID NO: 569) of the variable heavy chain region ofSEQ ID NO: 562; and the framework regions (SEQ ID NO: 583; SEQ ID NO:585; SEQ ID NO: 587; and SEQ ID NO: 589) of the variable light chainregion of SEQ ID NO: 582.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab15, comprising, or alternatively consisting of, SEQ ID NO:561 and SEQ ID NO: 581, or an antibody or antibody fragment comprisingthe CDRs of Ab15 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab15 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab15 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab15.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab15, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 562 and the variable lightchain sequence of SEQ ID NO: 582 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 562and/or SEQ ID NO: 582 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab15.In another embodiment of the invention, anti-HGF antibodies such as Ab15or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab15 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab16

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 601) QSVEESGGRLVTPGTPLTLTCTVSGIDLSNYAMGWVRQAPGKGLEYIGMIGVNGRAWYATWAKGRFTISKTSPTVDLKITSPTTEDTATYFCARLIDERSTYSYVFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 602) QSVEESGGRLVTPGTPLTLTCTVSGIDLSNYAMGWVRQAPGKGLEYIGMIGVNGRAWYATWAKGRFTISKTSPTVDLKITSPTTEDTATYFCARLIDERS TYSYVFDLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab16 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 610) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 621) QVLTQTPSPVSAAVGGTVTINCQGSQSLYNNNAFSWYQQKPGQPPKLLIYDASTLASGVPSRFKGSGSGTQFTLTISGVQCADAATYYCQGEFSCGDVDCIAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 622) QVLTQTPSPVSAAVGGTVTINCQGSQSLYNNNAFSWYQQKPGQPPKLLIYDASTLASGVPSRFKGSGSGTQFTLTISGVQCADAATYYCQGEFSCGDVDC IAFGGGTEVVV KR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab16 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 630) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 604; SEQ ID NO: 606;and SEQ ID NO: 608 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 601 or which contain the variable heavy chain sequence of SEQID NO: 602, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 624; SEQ ID NO: 626; and SEQ ID NO:628 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 621or which contain the variable light chain sequence of SEQ ID NO: 622, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 603; SEQ ID NO: 605; SEQ ID NO: 607; and SEQ IDNO: 609 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 601 or the variableheavy chain sequence of SEQ ID NO: 602, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 623; SEQ ID NO: 625; SEQ IDNO: 627; and SEQ ID NO: 629 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 621or the variable light chain sequence of SEQ ID NO: 622, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 601 or SEQ ID NO: 602 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 621 orSEQ ID NO: 622 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 604; SEQ ID NO: 606; and SEQ ID NO: 608 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 601 or the variable heavy chainsequence of SEQ ID NO: 602 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 624; SEQ ID NO: 626; and SEQ ID NO: 628 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 621 or the variable light chainsequence of SEQ ID NO: 622 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 603; SEQ ID NO: 605; SEQ ID NO: 607; and SEQ ID NO: 609 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 601 or the variable heavy chainsequence of SEQ ID NO: 602 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 623; SEQ ID NO: 625; SEQ ID NO: 627; and SEQ IDNO: 629 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 621 or the variablelight chain sequence of SEQ ID NO: 622 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 602; the variable light chain region of SEQID NO: 622; the complementarity-determining regions (SEQ ID NO: 604; SEQID NO: 606; and SEQ ID NO: 608) of the variable heavy chain region ofSEQ ID NO: 602; and the complementarity-determining regions (SEQ ID NO:624; SEQ ID NO: 626; and SEQ ID NO: 628) of the variable light chainregion of SEQ ID NO: 622 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 602; the variable light chain region of SEQID NO: 622; the framework regions (SEQ ID NO: 603; SEQ ID NO: 605; SEQID NO: 607; and SEQ ID NO: 609) of the variable heavy chain region ofSEQ ID NO: 602; and the framework regions (SEQ ID NO: 623; SEQ ID NO:625; SEQ ID NO: 627; and SEQ ID NO: 629) of the variable light chainregion of SEQ ID NO: 622.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab16, comprising, or alternatively consisting of, SEQ ID NO:601 and SEQ ID NO: 621, or an antibody or antibody fragment comprisingthe CDRs of Ab16 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab16 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab16 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab16.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab16, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 602 and the variable lightchain sequence of SEQ ID NO: 622 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 602and/or SEQ ID NO: 622 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab16.In another embodiment of the invention, anti-HGF antibodies such as Ab16or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab16 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab17

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 641) QSVEESGGRLVPPGTPLTLTCTVSGIDLSSYAMGWVRQAPGKGLEYIGMIDVSGSTYYADWAKGRLTISKTPTTVDLEITSPTTEDTATYFCARLIDERSTYSYAFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 642) QSVEESGGRLVPPGTPLTLTCTVSGIDLSSYAMGWVRQAPGKGLEYIGMIDVSGSTYYADWAKGRLTISKTPTTVDLEITSPTTEDTATYFCARLIDERS TYSYAFDLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab17 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 650) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 661) QVLTQTPSPVSAAVGGTVTINCQASQSFYNNGAFSWYQQKPGQPPKLLIYDASTLASGVPSRFKGSGSGTQFTLTISGVQCGDAATYYCQGEFSCGSADCVAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 662) QVLTQTPSPVSAAVGGTVTINCQASQSFYNNGAFSWYQQKPGQPPKLLIYDASTLASGVPSRFKGSGSGTQFTLTISGVQCGDAATYYCQGEFSCGSADC VAFGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab17 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 670) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 644; SEQ ID NO: 646;and SEQ ID NO: 648 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 641 or which contain the variable heavy chain sequence of SEQID NO: 642, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 664; SEQ ID NO: 666; and SEQ ID NO:668 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 661or which contain the variable light chain sequence of SEQ ID NO: 662, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 643; SEQ ID NO: 645; SEQ ID NO: 647; and SEQ IDNO: 649 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 641 or the variableheavy chain sequence of SEQ ID NO: 642, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 663; SEQ ID NO: 665; SEQ IDNO: 667; and SEQ ID NO: 669 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 661or the variable light chain sequence of SEQ ID NO: 662, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 641 or SEQ ID NO: 642 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 661 orSEQ ID NO: 662 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 644; SEQ ID NO: 646; and SEQ ID NO: 648 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 641 or the variable heavy chainsequence of SEQ ID NO: 642 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 664; SEQ ID NO: 666; and SEQ ID NO: 668 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 661 or the variable light chainsequence of SEQ ID NO: 662 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 643; SEQ ID NO: 645; SEQ ID NO: 647; and SEQ ID NO: 649 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 641 or the variable heavy chainsequence of SEQ ID NO: 642 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 663; SEQ ID NO: 665; SEQ ID NO: 667; and SEQ IDNO: 669 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 661 or the variablelight chain sequence of SEQ ID NO: 662 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 642; the variable light chain region of SEQID NO: 662; the complementarity-determining regions (SEQ ID NO: 644; SEQID NO: 646; and SEQ ID NO: 648) of the variable heavy chain region ofSEQ ID NO: 642; and the complementarity-determining regions (SEQ ID NO:664; SEQ ID NO: 666; and SEQ ID NO: 668) of the variable light chainregion of SEQ ID NO: 662 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 642; the variable light chain region of SEQID NO: 662; the framework regions (SEQ ID NO: 643; SEQ ID NO: 645; SEQID NO: 647; and SEQ ID NO: 649) of the variable heavy chain region ofSEQ ID NO: 642; and the framework regions (SEQ ID NO: 663; SEQ ID NO:665; SEQ ID NO: 667; and SEQ ID NO: 669) of the variable light chainregion of SEQ ID NO: 662.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab17, comprising, or alternatively consisting of, SEQ ID NO:641 and SEQ ID NO: 661, or an antibody or antibody fragment comprisingthe CDRs of Ab17 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab17 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab17 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab17.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab17, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 642 and the variable lightchain sequence of SEQ ID NO: 662 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 642and/or SEQ ID NO: 662 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab17.In another embodiment of the invention, anti-HGF antibodies such as Ab17or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab17 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab18

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 681) QSLEESGGRLVTPGTPLTLTCTASGFSLSSYDMSWVRQAPGKGLEWIGIIYAGSASTWFASWVKGRFTISKTSTTVDLKMTSLTTEDTATYFCARVGYSGYGYDDNLDMWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK .

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 682) QSLEESGGRLVTPGTPLTLTCTASGFSLSSYDMSWVRQAPGKGLEWIGIIYAGSASTWFASWVKGRFTISKTSTTVDLKMTSLTTEDTATYFCARVGYSG YGYDDNLDMWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab18 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 690) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 701) AYDMTQTPASVEVAVGGTVTIKCQASQSISTALAWYQQKPGQRPKLLIYDASKLASGVSSRFKGSGSGAQFTLTISGVECADAATYYCHQGYSSSNVDNTFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 702) AYDMTQTPASVEVAVGGTVTIKCQASQSISTALAWYQQKPGQRPKLLIYDASKLASGVSSRFKGSGSGAQFTLTISGVECADAATYYCHQGYSSSNVDNT FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab18 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 710) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 684; SEQ ID NO: 686;and SEQ ID NO: 688 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 681 or which contain the variable heavy chain sequence of SEQID NO: 682, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 704; SEQ ID NO: 706; and SEQ ID NO:708 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 701or which contain the variable light chain sequence of SEQ ID NO: 702, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 683; SEQ ID NO: 685; SEQ ID NO: 687; and SEQ IDNO: 689 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 681 or the variableheavy chain sequence of SEQ ID NO: 682, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 703; SEQ ID NO: 705; SEQ IDNO: 707; and SEQ ID NO: 709 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 701or the variable light chain sequence of SEQ ID NO: 702, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 681 or SEQ ID NO: 682 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 701 orSEQ ID NO: 702 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 684; SEQ ID NO: 686; and SEQ ID NO: 688 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 681 or the variable heavy chainsequence of SEQ ID NO: 682 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 704; SEQ ID NO: 706; and SEQ ID NO: 708 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 701 or the variable light chainsequence of SEQ ID NO: 702 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 683; SEQ ID NO: 685; SEQ ID NO: 687; and SEQ ID NO: 689 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 681 or the variable heavy chainsequence of SEQ ID NO: 682 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 703; SEQ ID NO: 705; SEQ ID NO: 707; and SEQ IDNO: 709 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 701 or the variablelight chain sequence of SEQ ID NO: 702 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 682; the variable light chain region of SEQID NO: 702; the complementarity-determining regions (SEQ ID NO: 684; SEQID NO: 686; and SEQ ID NO: 688) of the variable heavy chain region ofSEQ ID NO: 682; and the complementarity-determining regions (SEQ ID NO:704; SEQ ID NO: 706; and SEQ ID NO: 708) of the variable light chainregion of SEQ ID NO: 702 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 682; the variable light chain region of SEQID NO: 702; the framework regions (SEQ ID NO: 683; SEQ ID NO: 685; SEQID NO: 687; and SEQ ID NO: 689) of the variable heavy chain region ofSEQ ID NO: 682; and the framework regions (SEQ ID NO: 703; SEQ ID NO:705; SEQ ID NO: 707; and SEQ ID NO: 709) of the variable light chainregion of SEQ ID NO: 702.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab18, comprising, or alternatively consisting of, SEQ ID NO:681 and SEQ ID NO: 701, or an antibody or antibody fragment comprisingthe CDRs of Ab18 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab18 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab18 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab18.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab18, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 682 and the variable lightchain sequence of SEQ ID NO: 702 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 682and/or SEQ ID NO: 702 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab18.In another embodiment of the invention, anti-HGF antibodies such as Ab18or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab18 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab19

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 721) QSVEESGGRLVTPGTPLTLTCTASGFSLSNYWMGWVRQAPGEGLEWIGTISYDGNTYYASWAKGRFTISRTSTTVDLKMTSLTTEDTAIYFCATVNYPDYSTGAFNIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 722) QSVEESGGRLVTPGTPLTLTCTASGFSLSNYWMGWVRQAPGEGLEWIGTISYDGNTYYASWAKGRFTISRTSTTVDLKMTSLTTEDTAIYFCATVNYPDY STGAFNIWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab19 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 730) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 741) DVVMTQTPASVSEPVGGTVTIKCQASQSIDNYLAWYQQKPGQRPRLLIYYTSTLASGVPSRFKGSGSGTEYTLTISDLECADAATYYCQFTAYYSTYIGAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 742) DVVMTQTPASVSEPVGGTVTIKCQASQSIDNYLAWYQQKPGQRPRLLIYYTSTLASGVPSRFKGSGSGTEYTLTISDLECADAATYYCQFTAYYSTYIGA FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab19 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 750) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 724; SEQ ID NO: 726;and SEQ ID NO: 728 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 721 or which contain the variable heavy chain sequence of SEQID NO: 722, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 744; SEQ ID NO: 746; and SEQ ID NO:748 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 741or which contain the variable light chain sequence of SEQ ID NO: 742, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 723; SEQ ID NO: 725; SEQ ID NO: 727; and SEQ IDNO: 729 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 721 or the variableheavy chain sequence of SEQ ID NO: 722, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 743; SEQ ID NO: 745; SEQ IDNO: 747; and SEQ ID NO: 749 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 741or the variable light chain sequence of SEQ ID NO: 742, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 721 or SEQ ID NO: 722 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 741 orSEQ ID NO: 742 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 724; SEQ ID NO: 726; and SEQ ID NO: 728 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 721 or the variable heavy chainsequence of SEQ ID NO: 722 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 744; SEQ ID NO: 746; and SEQ ID NO: 748 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 741 or the variable light chainsequence of SEQ ID NO: 742 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 723; SEQ ID NO: 725; SEQ ID NO: 727; and SEQ ID NO: 729 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 721 or the variable heavy chainsequence of SEQ ID NO: 722 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 743; SEQ ID NO: 745; SEQ ID NO: 747; and SEQ IDNO: 749 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 741 or the variablelight chain sequence of SEQ ID NO: 742 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 722; the variable light chain region of SEQID NO: 742; the complementarity-determining regions (SEQ ID NO: 724; SEQID NO: 726; and SEQ ID NO: 728) of the variable heavy chain region ofSEQ ID NO: 722; and the complementarity-determining regions (SEQ ID NO:744; SEQ ID NO: 746; and SEQ ID NO: 748) of the variable light chainregion of SEQ ID NO: 742 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 722; the variable light chain region of SEQID NO: 742; the framework regions (SEQ ID NO: 723; SEQ ID NO: 725; SEQID NO: 727; and SEQ ID NO: 729) of the variable heavy chain region ofSEQ ID NO: 722; and the framework regions (SEQ ID NO: 743; SEQ ID NO:745; SEQ ID NO: 747; and SEQ ID NO: 749) of the variable light chainregion of SEQ ID NO: 742.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab19, comprising, or alternatively consisting of, SEQ ID NO:721 and SEQ ID NO: 741, or an antibody or antibody fragment comprisingthe CDRs of Ab19 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab19 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab19 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab19.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab19, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 722 and the variable lightchain sequence of SEQ ID NO: 742 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 722and/or SEQ ID NO: 742 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab19.In another embodiment of the invention, anti-HGF antibodies such as Ab19or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab19 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab20

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 761) EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYWMGWVRQAPGKGLEWIGTISYDGNTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATVNYPDYSTGAFNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 762) EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYWMGWVRQAPGKGLEWIGTISYDGNTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATVNYPDYSTGAFNIWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab20 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 770) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 781) DIQMTQSPSSLSASVGDRVTITCQASQSIDNYLAWYQQKPGKVPKLLIYYTSTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQFTAYYSTYIGAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 782) DIQMTQSPSSLSASVGDRVTITCQASQSIDNYLAWYQQKPGKVPKLLIYYTSTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQFTAYYSTYIGA FGGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab20 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 790) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 764; SEQ ID NO: 766;and SEQ ID NO: 768 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 761 or which contain the variable heavy chain sequence of SEQID NO: 762, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 784; SEQ ID NO: 786; and SEQ ID NO:788 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 781or which contain the variable light chain sequence of SEQ ID NO: 782, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 763; SEQ ID NO: 765; SEQ ID NO: 767; and SEQ IDNO: 769 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 761 or the variableheavy chain sequence of SEQ ID NO: 762, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 783; SEQ ID NO: 785; SEQ IDNO: 787; and SEQ ID NO: 789 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 781or the variable light chain sequence of SEQ ID NO: 782, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 761 or SEQ ID NO: 762 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 781 orSEQ ID NO: 782 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 764; SEQ ID NO: 766; and SEQ ID NO: 768 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 761 or the variable heavy chainsequence of SEQ ID NO: 762 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 784; SEQ ID NO: 786; and SEQ ID NO: 788 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 781 or the variable light chainsequence of SEQ ID NO: 782 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 763; SEQ ID NO: 765; SEQ ID NO: 767; and SEQ ID NO: 769 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 761 or the variable heavy chainsequence of SEQ ID NO: 762 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 783; SEQ ID NO: 785; SEQ ID NO: 787; and SEQ IDNO: 789 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 781 or the variablelight chain sequence of SEQ ID NO: 782 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 762; the variable light chain region of SEQID NO: 782; the complementarity-determining regions (SEQ ID NO: 764; SEQID NO: 766; and SEQ ID NO: 768) of the variable heavy chain region ofSEQ ID NO: 762; and the complementarity-determining regions (SEQ ID NO:784; SEQ ID NO: 786; and SEQ ID NO: 788) of the variable light chainregion of SEQ ID NO: 782 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 762; the variable light chain region of SEQID NO: 782; the framework regions (SEQ ID NO: 763; SEQ ID NO: 765; SEQID NO: 767; and SEQ ID NO: 769) of the variable heavy chain region ofSEQ ID NO: 762; and the framework regions (SEQ ID NO: 783; SEQ ID NO:785; SEQ ID NO: 787; and SEQ ID NO: 789) of the variable light chainregion of SEQ ID NO: 782.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab20, comprising, or alternatively consisting of, SEQ ID NO:761 and SEQ ID NO: 781, or an antibody or antibody fragment comprisingthe CDRs of Ab20 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab20 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab20 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab20.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab20, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 762 and the variable lightchain sequence of SEQ ID NO: 782 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 762and/or SEQ ID NO: 782 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab20.In another embodiment of the invention, anti-HGF antibodies such as Ab20or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab20 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab21

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 801) QSVEESGGRLVTPGTPLTLTCTVSGFSLSTYYMSWVRQAPGKGLEWIGIIYVSGITDYARWAKGRFTISKTSTTVDLKMTSLTTEDTATYFCARHIDSSGWDGLGIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 802) QSVEESGGRLVTPGTPLTLTCTVSGFSLSTYYMSWVRQAPGKGLEWIGIIYVSGITDYARWAKGRFTISKTSTTVDLKMTSLTTEDTATYFCARHIDSSG WDGLGIWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab21 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 810) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 821) AYDMTQTPASVEVAVGGTVTIKCQASESISSYLNWYQQKLGQPPKLLIYRASTLTSGVSSRFKGSGSGTEYTLTISDLECADAATYYCQQTYGYSDTDNSFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 822) AYDMTQTPASVEVAVGGTVTIKCQASESISSYLNWYQQKLGQPPKLLIYRASTLTSGVSSRFKGSGSGTEYTLTISDLECADAATYYCQQTYGYSDTDNS FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab21 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 830) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 804; SEQ ID NO: 806;and SEQ ID NO: 808 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 801 or which contain the variable heavy chain sequence of SEQID NO: 802, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 824; SEQ ID NO: 826; and SEQ ID NO:828 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 821or which contain the variable light chain sequence of SEQ ID NO: 822, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 803; SEQ ID NO: 805; SEQ ID NO: 807; and SEQ IDNO: 809 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 801 or the variableheavy chain sequence of SEQ ID NO: 802, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 823; SEQ ID NO: 825; SEQ IDNO: 827; and SEQ ID NO: 829 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 821or the variable light chain sequence of SEQ ID NO: 822, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 801 or SEQ ID NO: 802 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 821 orSEQ ID NO: 822 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 804; SEQ ID NO: 806; and SEQ ID NO: 808 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 801 or the variable heavy chainsequence of SEQ ID NO: 802 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 824; SEQ ID NO: 826; and SEQ ID NO: 828 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 821 or the variable light chainsequence of SEQ ID NO: 822 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 803; SEQ ID NO: 805; SEQ ID NO: 807; and SEQ ID NO: 809 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 801 or the variable heavy chainsequence of SEQ ID NO: 802 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 823; SEQ ID NO: 825; SEQ ID NO: 827; and SEQ IDNO: 829 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 821 or the variablelight chain sequence of SEQ ID NO: 822 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 802; the variable light chain region of SEQID NO: 822; the complementarity-determining regions (SEQ ID NO: 804; SEQID NO: 806; and SEQ ID NO: 808) of the variable heavy chain region ofSEQ ID NO: 802; and the complementarity-determining regions (SEQ ID NO:824; SEQ ID NO: 826; and SEQ ID NO: 828) of the variable light chainregion of SEQ ID NO: 822 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 802; the variable light chain region of SEQID NO: 822; the framework regions (SEQ ID NO: 803; SEQ ID NO: 805; SEQID NO: 807; and SEQ ID NO: 809) of the variable heavy chain region ofSEQ ID NO: 802; and the framework regions (SEQ ID NO: 823; SEQ ID NO:825; SEQ ID NO: 827; and SEQ ID NO: 829) of the variable light chainregion of SEQ ID NO: 822.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab21, comprising, or alternatively consisting of, SEQ ID NO:801 and SEQ ID NO: 821, or an antibody or antibody fragment comprisingthe CDRs of Ab21 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab21 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab21 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab21.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab21, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 802 and the variable lightchain sequence of SEQ ID NO: 822 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 802and/or SEQ ID NO: 822 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab21.In another embodiment of the invention, anti-HGF antibodies such as Ab21or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab21 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab23

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 841) QSLEESGGRLVTPGTPLTLTCTASGFTIGRYYMSWVRQAPGKGLEWIGIIYTHGVNPDYASWAKGRFTISRPSTTVDLKITSPTTEDTATYFCARVGGFNDYSDIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 842) QSLEESGGRLVTPGTPLTLTCTASGFTIGRYYMSWVRQAPGKGLEWIGIIYTHGVNPDYASWAKGRFTISRPSTTVDLKITSPTTEDTATYFCARVGGFN DYSDIWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab23 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 850) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 861) AYDMTQTPASVEVAVGGTVTIKCQASESISTYLAWYQQKPGQPPKLLIYRASTLASGVSSRFKGSGSGTQFTLTISGVECADAATYYCQQGYSYSNVDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 862) AYDMTQTPASVEVAVGGTVTIKCQASESISTYLAWYQQKPGQPPKLLIYRASTLASGVSSRFKGSGSGTQFTLTISGVECADAATYYCQQGYSYSNVDNA FGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab23 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 870) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 844; SEQ ID NO: 846;and SEQ ID NO: 848 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 841 or which contain the variable heavy chain sequence of SEQID NO: 842, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 864; SEQ ID NO: 866; and SEQ ID NO:868 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 861or which contain the variable light chain sequence of SEQ ID NO: 862, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 843; SEQ ID NO: 845; SEQ ID NO: 847; and SEQ IDNO: 849 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 841 or the variableheavy chain sequence of SEQ ID NO: 842, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 863; SEQ ID NO: 865; SEQ IDNO: 867; and SEQ ID NO: 869 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 861or the variable light chain sequence of SEQ ID NO: 862, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 841 or SEQ ID NO: 842 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 861 orSEQ ID NO: 862 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 844; SEQ ID NO: 846; and SEQ ID NO: 848 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 841 or the variable heavy chainsequence of SEQ ID NO: 842 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 864; SEQ ID NO: 866; and SEQ ID NO: 868 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 861 or the variable light chainsequence of SEQ ID NO: 862 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 843; SEQ ID NO: 845; SEQ ID NO: 847; and SEQ ID NO: 849 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 841 or the variable heavy chainsequence of SEQ ID NO: 842 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 863; SEQ ID NO: 865; SEQ ID NO: 867; and SEQ IDNO: 869 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 861 or the variablelight chain sequence of SEQ ID NO: 862 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 842; the variable light chain region of SEQID NO: 862; the complementarity-determining regions (SEQ ID NO: 844; SEQID NO: 846; and SEQ ID NO: 848) of the variable heavy chain region ofSEQ ID NO: 842; and the complementarity-determining regions (SEQ ID NO:864; SEQ ID NO: 866; and SEQ ID NO: 868) of the variable light chainregion of SEQ ID NO: 862 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 842; the variable light chain region of SEQID NO: 862; the framework regions (SEQ ID NO: 843; SEQ ID NO: 845; SEQID NO: 847; and SEQ ID NO: 849) of the variable heavy chain region ofSEQ ID NO: 842; and the framework regions (SEQ ID NO: 863; SEQ ID NO:865; SEQ ID NO: 867; and SEQ ID NO: 869) of the variable light chainregion of SEQ ID NO: 862.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab23, comprising, or alternatively consisting of, SEQ ID NO:841 and SEQ ID NO: 861, or an antibody or antibody fragment comprisingthe CDRs of Ab23 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab23 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab23 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab23.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab23, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 842 and the variable lightchain sequence of SEQ ID NO: 862 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 842and/or SEQ ID NO: 862 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab23.In another embodiment of the invention, anti-HGF antibodies such as Ab23or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab23 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab24

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 881) EVQLVESGGGLVQPGGSLRLSCAASGFTVGRYYMSWVRQAPGKGLEWIGIIYTHGVNPDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVGGFNDYSDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 882) EVQLVESGGGLVQPGGSLRLSCAASGFTVGRYYMSWVRQAPGKGLEWIGIIYTHGVNPDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVG GFNDYSDIWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab24 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 890) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 901) DIQMTQSPSSLSASVGDRVTITCQASESISTYLAWYQQKPGKVPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGYSYSNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 902) DIQMTQSPSSLSASVGDRVTITCQASESISTYLAWYQQKPGKVPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGYSYSNVDNA FGGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab24 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 910) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 884; SEQ ID NO: 886;and SEQ ID NO: 888 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 881 or which contain the variable heavy chain sequence of SEQID NO: 882, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 904; SEQ ID NO: 906; and SEQ ID NO:908 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 901or which contain the variable light chain sequence of SEQ ID NO: 902, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 883; SEQ ID NO: 885; SEQ ID NO: 887; and SEQ IDNO: 889 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 881 or the variableheavy chain sequence of SEQ ID NO: 882, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 903; SEQ ID NO: 905; SEQ IDNO: 907; and SEQ ID NO: 909 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 901or the variable light chain sequence of SEQ ID NO: 902, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 881 or SEQ ID NO: 882 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 901 orSEQ ID NO: 902 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 884; SEQ ID NO: 886; and SEQ ID NO: 888 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 881 or the variable heavy chainsequence of SEQ ID NO: 882 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 904; SEQ ID NO: 906; and SEQ ID NO: 908 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 901 or the variable light chainsequence of SEQ ID NO: 902 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 883; SEQ ID NO: 885; SEQ ID NO: 887; and SEQ ID NO: 889 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 881 or the variable heavy chainsequence of SEQ ID NO: 882 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 903; SEQ ID NO: 905; SEQ ID NO: 907; and SEQ IDNO: 909 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 901 or the variablelight chain sequence of SEQ ID NO: 902 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 882; the variable light chain region of SEQID NO: 902; the complementarity-determining regions (SEQ ID NO: 884; SEQID NO: 886; and SEQ ID NO: 888) of the variable heavy chain region ofSEQ ID NO: 882; and the complementarity-determining regions (SEQ ID NO:904; SEQ ID NO: 906; and SEQ ID NO: 908) of the variable light chainregion of SEQ ID NO: 902 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 882; the variable light chain region of SEQID NO: 902; the framework regions (SEQ ID NO: 883; SEQ ID NO: 885; SEQID NO: 887; and SEQ ID NO: 889) of the variable heavy chain region ofSEQ ID NO: 882; and the framework regions (SEQ ID NO: 903; SEQ ID NO:905; SEQ ID NO: 907; and SEQ ID NO: 909) of the variable light chainregion of SEQ ID NO: 902.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab24, comprising, or alternatively consisting of, SEQ ID NO:881 and SEQ ID NO: 901, or an antibody or antibody fragment comprisingthe CDRs of Ab24 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab24 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab24 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab24.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab24, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 882 and the variable lightchain sequence of SEQ ID NO: 902 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 882and/or SEQ ID NO: 902 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab24.In another embodiment of the invention, anti-HGF antibodies such as Ab24or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab24 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab25

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 921) QSLEESGGRLVTPGTPLTLTCTASGFSLSSYAMGWFRQAPGKGLEWIAYIFASGSTYYASWAKGRFTISKTSTTVELKITSLTTEDTATYFCARGSGARFFPNYFAIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 922) QSLEESGGRLVTPGTPLTLTCTASGFSLSSYAMGWFRQAPGKGLEWIAYIFASGSTYYASWAKGRFTISKTSTTVELKITSLTTEDTATYFCARGSGARF FPNYFAIWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab25 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 930) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 941) QVLTQTASSVSAAVGGTVTISCQSSQSVTNNNDLAWYQQKPGQPPKLLIYQASKLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCQGSYSGGICAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 942) QVLTQTASSVSAAVGGTVTISCQSSQSVTNNNDLAWYQQKPGQPPKLLIYQASKLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCQGSYSGGICAF GGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab25 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 950) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 924; SEQ ID NO: 926;and SEQ ID NO: 928 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 921 or which contain the variable heavy chain sequence of SEQID NO: 922, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 944; SEQ ID NO: 946; and SEQ ID NO:948 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 941or which contain the variable light chain sequence of SEQ ID NO: 942, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 923; SEQ ID NO: 925; SEQ ID NO: 927; and SEQ IDNO: 929 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 921 or the variableheavy chain sequence of SEQ ID NO: 922, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 943; SEQ ID NO: 945; SEQ IDNO: 947; and SEQ ID NO: 949 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 941or the variable light chain sequence of SEQ ID NO: 942, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 921 or SEQ ID NO: 922 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 941 orSEQ ID NO: 942 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 924; SEQ ID NO: 926; and SEQ ID NO: 928 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 921 or the variable heavy chainsequence of SEQ ID NO: 922 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 944; SEQ ID NO: 946; and SEQ ID NO: 948 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 941 or the variable light chainsequence of SEQ ID NO: 942 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 923; SEQ ID NO: 925; SEQ ID NO: 927; and SEQ ID NO: 929 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 921 or the variable heavy chainsequence of SEQ ID NO: 922 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 943; SEQ ID NO: 945; SEQ ID NO: 947; and SEQ IDNO: 949 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 941 or the variablelight chain sequence of SEQ ID NO: 942 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 922; the variable light chain region of SEQID NO: 942; the complementarity-determining regions (SEQ ID NO: 924; SEQID NO: 926; and SEQ ID NO: 928) of the variable heavy chain region ofSEQ ID NO: 922; and the complementarity-determining regions (SEQ ID NO:944; SEQ ID NO: 946; and SEQ ID NO: 948) of the variable light chainregion of SEQ ID NO: 942 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 922; the variable light chain region of SEQID NO: 942; the framework regions (SEQ ID NO: 923; SEQ ID NO: 925; SEQID NO: 927; and SEQ ID NO: 929) of the variable heavy chain region ofSEQ ID NO: 922; and the framework regions (SEQ ID NO: 943; SEQ ID NO:945; SEQ ID NO: 947; and SEQ ID NO: 949) of the variable light chainregion of SEQ ID NO: 942.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab25, comprising, or alternatively consisting of, SEQ ID NO:921 and SEQ ID NO: 941, or an antibody or antibody fragment comprisingthe CDRs of Ab25 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab25 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab25 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab25.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab25, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 922 and the variable lightchain sequence of SEQ ID NO: 942 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 922and/or SEQ ID NO: 942 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab25.In another embodiment of the invention, anti-HGF antibodies such as Ab25or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab25 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab26

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 961) QSVEESGGRLVTPGTPLTLTCTVSGFSLSTYTMNWVRQAPGKGLEYIGFISSSSSIDYVSWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARDFYADYIGGGYPYIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 962) QSVEESGGRLVTPGTPLTLTCTVSGFSLSTYTMNWVRQAPGKGLEYIGFISSSSSIDYVSWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARDFYADY IGGGYPYIWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab26 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 970) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 981) ADVVMTQTPASVSEPVGGTVTIKCQASQSISSYLSWYQQKPGQPPKLLIYGASKLTSGVPSRFKGSGSGTEYTLTISDLECADAATYYCQSNYDIYSYAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 982) ADVVMTQTPASVSEPVGGTVTIKCQASQSISSYLSWYQQKPGQPPKLLIYGASKLTSGVPSRFKGSGSGTEYTLTISDLECADAATYYCQSNYDIYSYAF GGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab26 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 990) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 964; SEQ ID NO: 966;and SEQ ID NO: 968 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 961 or which contain the variable heavy chain sequence of SEQID NO: 962, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 984; SEQ ID NO: 986; and SEQ ID NO:988 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain sequence of SEQ ID NO: 981or which contain the variable light chain sequence of SEQ ID NO: 982, orantibodies or fragments containing combinations of sequences which areat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical thereto. Inanother embodiment of the invention, the antibodies of the invention orfragments thereof comprise, or alternatively consist of, combinations ofone or more of the exemplified variable heavy chain and variable lightchain sequences, or the heavy chain and light chain sequences set forthabove, or sequences that are at least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 963; SEQ ID NO: 965; SEQ ID NO: 967; and SEQ IDNO: 969 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 961 or the variableheavy chain sequence of SEQ ID NO: 962, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 983; SEQ ID NO: 985; SEQ IDNO: 987; and SEQ ID NO: 989 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 981or the variable light chain sequence of SEQ ID NO: 982, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 961 or SEQ ID NO: 962 or polypeptides that are atleast 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 981 orSEQ ID NO: 982 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 964; SEQ ID NO: 966; and SEQ ID NO: 968 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 961 or the variable heavy chainsequence of SEQ ID NO: 962 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 984; SEQ ID NO: 986; and SEQ ID NO: 988 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 981 or the variable light chainsequence of SEQ ID NO: 982 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 963; SEQ ID NO: 965; SEQ ID NO: 967; and SEQ ID NO: 969 whichcorrespond to the framework regions (FRs or constant regions) of theheavy chain sequence of SEQ ID NO: 961 or the variable heavy chainsequence of SEQ ID NO: 962 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 983; SEQ ID NO: 985; SEQ ID NO: 987; and SEQ IDNO: 989 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 981 or the variablelight chain sequence of SEQ ID NO: 982 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 962; the variable light chain region of SEQID NO: 982; the complementarity-determining regions (SEQ ID NO: 964; SEQID NO: 966; and SEQ ID NO: 968) of the variable heavy chain region ofSEQ ID NO: 962; and the complementarity-determining regions (SEQ ID NO:984; SEQ ID NO: 986; and SEQ ID NO: 988) of the variable light chainregion of SEQ ID NO: 982 or sequences that are at least 90% or 95%identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 962; the variable light chain region of SEQID NO: 982; the framework regions (SEQ ID NO: 963; SEQ ID NO: 965; SEQID NO: 967; and SEQ ID NO: 969) of the variable heavy chain region ofSEQ ID NO: 962; and the framework regions (SEQ ID NO: 983; SEQ ID NO:985; SEQ ID NO: 987; and SEQ ID NO: 989) of the variable light chainregion of SEQ ID NO: 982.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab26, comprising, or alternatively consisting of, SEQ ID NO:961 and SEQ ID NO: 981, or an antibody or antibody fragment comprisingthe CDRs of Ab26 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab26 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab26 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab26.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab26, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 962 and the variable lightchain sequence of SEQ ID NO: 982 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 962and/or SEQ ID NO: 982 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab26.In another embodiment of the invention, anti-HGF antibodies such as Ab26or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab26 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab27

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 1001) QSLEESGGDLVKPGGTLTLTCTASGFSFSDDHYMCWVRQAPGKGLQWIACMYVGSSGATYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARDDWTSYYAWGYWALWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 1002) QSLEESGGDLVKPGGTLTLTCTASGFSFSDDHYMCWVRQAPGKGLQWIACMYVGSSGATYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARDDWTSYYAWGYWALWGPGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab27 and which contain a constant heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 1010) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

(SEQ ID NO: 1021) ADIVMTQNPASVSEPVGGTVTIKCQASQSVNSWLSWYQQKPGQPPKFLIYKASTLASGVSSRFKGSGIGTEFTLTISDLECADAATYYCQFSNSGTIYGSGFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 1022) ADIVMTQNPASVSEPVGGTVTIKCQASQSVNSWLSWYQQKPGQPPKFLIYKASTLASGVSSRFKGSGIGTEFTLTISDLECADAATYYCQFSNSGTIYGS GFGGGTEVVVKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab27 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 1030) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 1004; SEQ ID NO: 1006;and SEQ ID NO: 1008 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 1001 or which contain the variable heavy chain sequence ofSEQ ID NO: 1002, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 1024; SEQ ID NO: 1026; and SEQ IDNO: 1028 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the light chain sequence of SEQ IDNO: 1021 or which contain the variable light chain sequence of SEQ IDNO: 1022, or antibodies or fragments containing combinations ofsequences which are at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%identical thereto. In another embodiment of the invention, theantibodies of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the exemplifiedvariable heavy chain and variable light chain sequences, or the heavychain and light chain sequences set forth above, or sequences that areat least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 1003; SEQ ID NO: 1005; SEQ ID NO: 1007; and SEQID NO: 1009 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 1001 or the variableheavy chain sequence of SEQ ID NO: 1002, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 1023; SEQ ID NO: 1025; SEQ IDNO: 1027; and SEQ ID NO: 1029 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 1021or the variable light chain sequence of SEQ ID NO: 1022, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 1001 or SEQ ID NO: 1002 or polypeptides that areat least 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 1021 orSEQ ID NO: 1022 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 1004; SEQ ID NO: 1006; and SEQ ID NO: 1008 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 1001 or the variable heavy chainsequence of SEQ ID NO: 1002 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 1024; SEQ ID NO: 1026; and SEQ ID NO: 1028 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 1021 or the variable light chainsequence of SEQ ID NO: 1022 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 1003; SEQ ID NO: 1005; SEQ ID NO: 1007; and SEQ ID NO: 1009which correspond to the framework regions (FRs or constant regions) ofthe heavy chain sequence of SEQ ID NO: 1001 or the variable heavy chainsequence of SEQ ID NO: 1002 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 1023; SEQ ID NO: 1025; SEQ ID NO: 1027; and SEQID NO: 1029 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 1021 or the variablelight chain sequence of SEQ ID NO: 1022 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 1002; the variable light chain region of SEQID NO: 1022; the complementarity-determining regions (SEQ ID NO: 1004;SEQ ID NO: 1006; and SEQ ID NO: 1008) of the variable heavy chain regionof SEQ ID NO: 1002; and the complementarity-determining regions (SEQ IDNO: 1024; SEQ ID NO: 1026; and SEQ ID NO: 1028) of the variable lightchain region of SEQ ID NO: 1022 or sequences that are at least 90% or95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 1002; the variable light chain region of SEQID NO: 1022; the framework regions (SEQ ID NO: 1003; SEQ ID NO: 1005;SEQ ID NO: 1007; and SEQ ID NO: 1009) of the variable heavy chain regionof SEQ ID NO: 1002; and the framework regions (SEQ ID NO: 1023; SEQ IDNO: 1025; SEQ ID NO: 1027; and SEQ ID NO: 1029) of the variable lightchain region of SEQ ID NO: 1022.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab27, comprising, or alternatively consisting of, SEQ ID NO:1001 and SEQ ID NO: 1021, or an antibody or antibody fragment comprisingthe CDRs of Ab27 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab27 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab27 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab27.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab27, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 1002 and the variable lightchain sequence of SEQ ID NO: 1022 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 1002and/or SEQ ID NO: 1022 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab27.In another embodiment of the invention, anti-HGF antibodies such as Ab27or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab27 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

Antibody Ab28

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess a heavy chainsequence comprising the sequence set forth below:

(SEQ ID NO: 1041) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNAISWVRQAPGKGLEWVGVIYVIGVTDYASSAQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYDSGWNHFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In one embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variableheavy chain sequence comprising the sequence set forth below:

(SEQ ID NO: 1042) EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNAISWVRQAPGKGLEWVGVIYVIGVTDYASSAQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVYD SGWNHFNLWGQGTLVTVSS.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that possess the sameepitopic specificity as Ab28 and which contain a constant heavy chainsequence comprising the sequence set forth below:

SEQ ID NO: 1050) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a light chainsequence comprising the sequence set forth below:

SEQ ID NO: 1061) DIQMTQSPSTLSASVGDRVTITCQASQSISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVANVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain a variablelight chain sequence comprising the sequence set forth below:

(SEQ ID NO: 1062) DIQMTQSPSTLSASVGDRVTITCQASQSISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQAYSVANVDNA FGGGTKVEIKR.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that bind the same epitopeas Ab28 which contain a constant light chain sequence comprising thesequence set forth below:

(SEQ ID NO: 1070) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

In another embodiment, the invention includes antibodies and antibodyfragments having binding specificity to HGF that contain one, two, orthree of the polypeptide sequences of SEQ ID NO: 1044; SEQ ID NO: 1046;and SEQ ID NO: 1048 which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain sequence ofSEQ ID NO: 1041 or which contain the variable heavy chain sequence ofSEQ ID NO: 1042, and/or which further contain one, two, or three of thepolypeptide sequences of SEQ ID NO: 1064; SEQ ID NO: 1066; and SEQ IDNO: 1068 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the light chain sequence of SEQ IDNO: 1061 or which contain the variable light chain sequence of SEQ IDNO: 1062, or antibodies or fragments containing combinations ofsequences which are at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%identical thereto. In another embodiment of the invention, theantibodies of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the exemplifiedvariable heavy chain and variable light chain sequences, or the heavychain and light chain sequences set forth above, or sequences that areat least 90% or 95% identical thereto.

The invention further contemplates anti-HGF antibodies and antibodyfragments comprising one, two, three, or four of the polypeptidesequences of SEQ ID NO: 1043; SEQ ID NO: 1045; SEQ ID NO: 1047; and SEQID NO: 1049 which correspond to the framework regions (FRs or constantregions) of the heavy chain sequence of SEQ ID NO: 1041 or the variableheavy chain sequence of SEQ ID NO: 1042, and/or one, two, three, or fourof the polypeptide sequences of SEQ ID NO: 1063; SEQ ID NO: 1065; SEQ IDNO: 1067; and SEQ ID NO: 1069 which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 1061or the variable light chain sequence of SEQ ID NO: 1062, or combinationsof these polypeptide sequences or sequences which are at least 80%, 90%or 95% identical therewith.

In another embodiment of the invention, the antibodies and antibodyfragments of the invention or fragments thereof comprise, oralternatively consist of, combinations of one or more of the FRs, CDRs,the variable heavy chain and variable light chain sequences, and theheavy chain and light chain sequences set forth above, including all ofthem or sequences which are at least 90% or 95% identical thereto.

In another embodiment of the invention, the anti-HGF antibody fragmentsof the invention comprise, or alternatively consist of, the polypeptidesequence of SEQ ID NO: 1041 or SEQ ID NO: 1042 or polypeptides that areat least 90% or 95% identical thereto. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO: 1061 orSEQ ID NO: 1062 or polypeptides that are at least 90% or 95% identicalthereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 1044; SEQ ID NO: 1046; and SEQ ID NO: 1048 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe heavy chain sequence of SEQ ID NO: 1041 or the variable heavy chainsequence of SEQ ID NO: 1042 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, or three of the polypeptide sequences of SEQ IDNO: 1064; SEQ ID NO: 1066; and SEQ ID NO: 1068 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 1061 or the variable light chainsequence of SEQ ID NO: 1062 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the antibody or antibodyfragment having binding specificity to HGF comprises, or alternativelyconsists of, one, two, three, or four of the polypeptide sequences ofSEQ ID NO: 1043; SEQ ID NO: 1045; SEQ ID NO: 1047; and SEQ ID NO: 1049which correspond to the framework regions (FRs or constant regions) ofthe heavy chain sequence of SEQ ID NO: 1041 or the variable heavy chainsequence of SEQ ID NO: 1042 or sequences that are at least 90% or 95%identical thereto.

In a further embodiment of the invention, the subject antibody orantibody fragment having binding specificity to HGF comprises, oralternatively consists of, one, two, three, or four of the polypeptidesequences of SEQ ID NO: 1063; SEQ ID NO: 1065; SEQ ID NO: 1067; and SEQID NO: 1069 which correspond to the framework regions (FRs or constantregions) of the light chain sequence of SEQ ID NO: 1061 or the variablelight chain sequence of SEQ ID NO: 1062 or sequences that are at least90% or 95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 1042; the variable light chain region of SEQID NO: 1062; the complementarity-determining regions (SEQ ID NO: 1044;SEQ ID NO: 1046; and SEQ ID NO: 1048) of the variable heavy chain regionof SEQ ID NO: 1042; and the complementarity-determining regions (SEQ IDNO: 1064; SEQ ID NO: 1066; and SEQ ID NO: 1068) of the variable lightchain region of SEQ ID NO: 1062 or sequences that are at least 90% or95% identical thereto.

The invention also contemplates antibody fragments that include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toHGF comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable heavychain region of SEQ ID NO: 1042; the variable light chain region of SEQID NO: 1062; the framework regions (SEQ ID NO: 1043; SEQ ID NO: 1045;SEQ ID NO: 1047; and SEQ ID NO: 1049) of the variable heavy chain regionof SEQ ID NO: 1042; and the framework regions (SEQ ID NO: 1063; SEQ IDNO: 1065; SEQ ID NO: 1067; and SEQ ID NO: 1069) of the variable lightchain region of SEQ ID NO: 1062.

In a particularly preferred embodiment of the invention, the anti-HGFantibody is Ab28, comprising, or alternatively consisting of, SEQ ID NO:1041 and SEQ ID NO: 1061, or an antibody or antibody fragment comprisingthe CDRs of Ab28 and having at least one of the biological activitiesset forth herein or is an anti-HGF antibody that competes with Ab28 inbinding HGF, preferably one containing sequences that are at least 90%or 95% identical to that of Ab28 or an antibody that binds to the sameor overlapping epitope(s) on HGF as Ab28.

In a further particularly preferred embodiment of the invention,antibody fragments comprise, or alternatively consist of, Fab (fragmentantigen binding) fragments having binding specificity for HGF. Withrespect to antibody Ab28, the Fab fragment preferably includes thevariable heavy chain sequence of SEQ ID NO: 1042 and the variable lightchain sequence of SEQ ID NO: 1062 or sequences that are at least 90% or95% identical thereto. This embodiment of the invention further includesFabs containing additions, deletions, and variants of SEQ ID NO: 1042and/or SEQ ID NO: 1062 which retain the binding specificity for HGF.

In one embodiment of the invention described herein (infra), Fabfragments may be produced by enzymatic digestion (e.g., papain) of Ab28.In another embodiment of the invention, anti-HGF antibodies such as Ab28or Fab fragments thereof may be produced via expression in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example haploid or diploid yeast suchas haploid or diploid Pichia) and other yeast strains. Suitable Pichiaspecies include, but are not limited to, Pichia pastoris.

In an additional embodiment, the invention is further directed topolynucleotides encoding antibody polypeptides having bindingspecificity to HGF, including the heavy and/or light chains of Ab28 aswell as fragments, variants, combinations of one or more of the FRs,CDRs, the variable heavy chain and variable light chain sequences, andthe heavy chain and light chain sequences set forth above, including allof them or sequences which are at least 90% or 95% identical thereto.

In another embodiment, the invention contemplates an isolated anti-HGFantibody comprising any of the afore-identified V_(H) polypeptidesequences; and further comprising any of the afore-identified V_(L)polypeptide sequence, wherein one or more of the framework residues (FRresidues) in said V_(H) or V_(L) polypeptide has been substituted withanother amino acid residue resulting in an anti-HGF antibody thatspecifically binds HGF. The invention contemplates humanized andchimeric forms of these antibodies. The chimeric antibodies may includean Fc derived from IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9,IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19constant regions.

In one embodiment of the invention, the antibodies or V_(H) or V_(L)polypeptides originate or are selected from one or more rabbit B cellpopulations prior to initiation of the humanization process referencedherein.

In another embodiment of the invention, the anti-HGF antibodies andfragments thereof which have binding specificity for human HGF andpotentially to allelic variants of human HGF may also bind to non-humanHGF polypeptides including primate homologs of human HGF such as HGFexpressed in chimpanzee, monkey, ape, gibbon, gorilla, lemur and otherprimates, and potentially to non-primate HGF polypeptides such asrabbit, canine, rodent, feline, and other HGF species homologs.

In another embodiment of the invention, the anti-HGF antibodies andfragments thereof do not have binding specificity for HGF-R (c-met). Ina further embodiment of the invention, the anti-HGF antibodies andfragments thereof inhibit the association of HGF with HGF-R or inhibitHGF-R or c-met. In another embodiment of the invention, the anti-HGFantibodies and fragments thereof inhibit the association of HGF withHGF-R and/or multimers thereof and/or antagonize at least one of thebiological effects thereof.

In addition, the subject anti-HGF antibodies and fragments thereof maybe modified post-translationally to add effector moieties such aschemical linkers, detectable moieties such as for example fluorescentdyes, enzymes, substrates, bioluminescent materials, radioactivematerials, and chemiluminescent moieties, or functional moieties such asfor example streptavidin, avidin, biotin, a cytotoxin, a cytotoxicagent, and radioactive materials.

Regarding detectable moieties, further exemplary enzymes include, butare not limited to, horseradish peroxidase, acetylcholinesterase,alkaline phosphatase, beta-galactosidase and luciferase. Furtherexemplary fluorescent materials include, but are not limited to,rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone,dichlorotriazinylamine, phycoerythrin and dansyl chloride. Furtherexemplary chemiluminescent moieties include, but are not limited to,luminol. Further exemplary bioluminescent materials include, but are notlimited to, luciferin and aequorin. Further exemplary radioactivematerials include, but are not limited to, Iodine 125 (¹²⁵I), Carbon 14(¹⁴C), Sulfur 35 (³⁵S), Tritium (³H) and Phosphorus 32 (³²P).

In another embodiment the subject anti-HGF antibodies and fragments maybe attached or administered in combination therapies with one or moreother functional moieties, exemplary cytotoxic agents include, but arenot limited to, methotrexate, aminopterin, 6-mercaptopurine,6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agentssuch as mechlorethamine, thioepa chlorambucil, melphalan, carmustine(BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea,cyclothosphamide, mechlorethamine, busulfan, dibromomannitol,streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP)cisplatin and carboplatin (paraplatin); anthracyclines includedaunorubicin (formerly daunomycin), doxorubicin (adriamycin),detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone andbisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin,calicheamicin, mithramycin, and anthramycin (AMC); and antimytoticagents such as the vinca alkaloids, vincristine and vinblastine. Othercytotoxic agents include paclitaxel (taxol), ricin, pseudomonasexotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide,emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione,1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine,propranolol, puromycin, procarbazine, hydroxyurea, asparaginase,corticosteroids, mytotane (O,P′-(DDD)), interferons, and mixtures ofthese cytotoxic agents.

Further cytotoxic agents include, but are not limited to,chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel,gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, mitomycin C,actinomycin D, cyclophosphamide, vincristine and bleomycin. Toxicproteins from plants and bacteria such as ricin, diphtheria toxin andPseudomonas toxin may be conjugated to the humanized or chimericantibodies, or binding fragments thereof, to generatecell-type-specific-killing reagents (Youle, et al., Proc. Nat'l Acad.Sci. USA 77:5483 (1980); Gilliland, et al., Proc. Nat'l Acad. Sci. USA77:4539 (1980); Krolick, et al., Proc. Nat'l Acad. Sci. USA 77:5419(1980)).

Other cytotoxic agents which may be used in combination with the subjectanti-HGF antibodies and fragments include cytotoxic ribonucleases asdescribed by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of theinvention also relate to radioimmunoconjugates where a radionuclide thatemits alpha or beta particles is stably coupled to the antibody, orbinding fragments thereof, with or without the use of a complex-formingagent. Such radionuclides include beta-emitters such as Phosphorus-32(³²P), Scandium-47 (⁴⁷Sc), Copper-67 (⁶⁷Cu), Gallium-67 (⁶⁷Ga),Yttrium-88 (⁸⁸Y), Yttrium-90 (⁹⁰Y), Iodine-125 (¹²⁵I), Iodine-131 (¹³¹I)Samarium-153 (¹⁵³5 m), Lutetium-177 (¹⁷⁷Lu), Rhenium-186 (¹⁸⁶Re) orRhenium-188 (¹⁸⁸Re), and alpha-emitters such as Astatine-211 (²¹¹At),Lead-212 (²¹²Pb) Bismuth-212 (²¹²Bi) or -213 (²¹³Bi) or Actinium-225(²²⁵Ac). The term “cytotoxic agent” as used herein broadly includes anysubstance that inhibits or prevents the function of cells and/or causesdestruction of cells and “chemotherapeutic agent” useful in thetreatment of cancer The term is intended to include radioactiveisotopes, chemotherapeutic agents e.g. methotrexate, adriamicin, vincaalkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan,mitomycin C, chlorambucil, daunorubicin or other intercalating agents,enzymes and fragments thereof such as nucleolytic enzymes, antibiotics,and toxins such as small molecule toxins or enzymatically active toxinsof bacterial, fungal, plant or animal origin, including fragments and/orvariants thereof, and the various antitumor or anticancer agentsdisclosed below. Other cytotoxic agents are described below. Atumoricidal agent causes destruction of tumor cells. A “chemotherapeuticagent” is a chemical compound useful in the treatment of cancer.Examples of chemotherapeutic agents include alkylating agents such asthiotepa and CYTOXAN®. cyclosphosphamide; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (particularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammall and calicheamicinomegaI1 (see, e.g., Agnew, Chem Intl. Ed. Engl., 33: 183-186 (1994));dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®doxorubicin (including morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™Cremophor-free, albumin-engineered nanoparticle formulation ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin;aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid;capecitabine; and pharmaceutically acceptable salts, acids orderivatives of any of the above. Also included in the definition of“chemotherapeutic agent” above are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogens andselective estrogen receptor modulators (SERMs), including, for example,tamoxifen (including NOLVADEX® tamoxifen), raloxifene, droloxifene,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andFARESTON. toremifene; aromatase inhibitors that inhibit the enzymearomatase, which regulates estrogen production in the adrenal glands,such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE®megestrol acetate, AROMASIN® exemestane, formestanie, fadrozole,RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole; andanti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide,and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleosidecytosine analog); antisense oligonucleotides, particularly those whichinhibit expression of genes in signaling pathways implicated in abherantcell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras;ribozymes such as a VEGF expression inhibitor (e.g., ANGIOZYME®ribozyme) and a HER2 expression inhibitor; vaccines such as gene therapyvaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, andVAXID® vaccine; PROLEUKIN® rIL-2; LURTOTECAN® topoisomerase 1 inhibitor;ABARELIX® rmRH; and pharmaceutically acceptable salts, acids orderivatives of any of the above. Preferred examples of cytotoxic agentsused in association with the subject anti-HGF antibodies and fragmentsare Erlotinib, Gemcitabine, Premetrexed, Docetaxel, Folfox ChemotherapyRegime Combinations, Paclitaxel And Bevacizumab.

Methods are known in the art for conjugating an antibody or bindingfragment thereof to a detectable moiety and the like, such as forexample those methods described by Hunter et al, Nature 144:945 (1962);David et al, Biochemistry 13:1014 (1974); Pain et al, J. Immunol. Meth.40:219 (1981); and Nygren, J., Histochem. and Cytochem. 30:407 (1982).

Embodiments described herein further include variants and equivalentsthat are substantially homologous to the antibodies, antibody fragments,diabodies, SMIPs, camelbodies, nanobodies, IgNAR, polypeptides, variableregions and CDRs set forth herein. These may contain, e.g., conservativesubstitution mutations, (i.e., the substitution of one or more aminoacids by similar amino acids). For example, conservative substitutionrefers to the substitution of an amino acid with another within the samegeneral class, e.g., one acidic amino acid with another acidic aminoacid, one basic amino acid with another basic amino acid, or one neutralamino acid by another neutral amino acid. What is intended by aconservative amino acid substitution is well known in the art.

In another embodiment, the invention contemplates polypeptide sequenceshaving at least 90% or greater sequence homology to any one or more ofthe polypeptide sequences of antibody fragments, variable regions andCDRs set forth herein. More preferably, the invention contemplatespolypeptide sequences having at least 95% or greater sequence homology,even more preferably at least 98% or greater sequence homology, andstill more preferably at least 99% or greater sequence homology to anyone or more of the polypeptide sequences of antibody fragments, variableregions and CDRs set forth herein. Methods for determining homologybetween nucleic acid and amino acid sequences are well known to those ofordinary skill in the art.

In another embodiment, the invention further contemplates theabove-recited polypeptide homologs of the antibody fragments, variableregions and CDRs set forth herein further having anti-HGF activity.Non-limiting examples of anti-HGF activity are set forth herein, forexample, in the working examples infra.

In another embodiment, the invention further contemplates the generationand use of anti-idiotypic antibodies that bind any of the foregoingsequences. In an exemplary embodiment, such an anti-idiotypic antibodycould be administered to a subject who has received an anti-HGF antibodyto modulate, reduce, or neutralize, the effect of the anti-HGF antibody.Such anti-idiotypic antibodies could also be useful for treatment of anautoimmune disease characterized by the presence of anti-HGF antibodies.A further exemplary use of such anti-idiotypic antibodies is fordetection of the anti-HGF antibodies of the present invention, forexample to monitor the levels of the anti-HGF antibodies present in asubject's blood or other bodily fluids.

The present invention also contemplates anti-HGF antibodies comprisingany of the polypeptide or polynucleotide sequences described hereinsubstituted for any of the other polynucleotide sequences describedherein. For example, without limitation thereto, the present inventioncontemplates antibodies comprising the combination of any of thevariable light chain and variable heavy chain sequences describedherein, and further contemplates antibodies resulting from substitutionof any of the CDR sequences described herein for any of the other CDRsequences described herein.

Additional Exemplary Embodiments of the Invention

In another embodiment, the invention contemplates one or more anti-humanHGF antibodies or antibody fragments which specifically bind to the samelinear or conformational epitope(s) and/or competes for binding to thesame linear or conformational epitope(s) on an intact human HGFpolypeptide or fragment thereof as an anti-human HGF antibody selectedfrom the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8,Ab9, Ab10, Ab11, Ab12, Ab13 Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20,Ab21, Ab23, Ab24, Ab25, Ab26, Ab27 and Ab28. In a preferred embodiment,the anti-human HGF antibody or fragment specifically binds to the samelinear or conformational epitope(s) and/or competes for binding to thesame linear or conformational epitope(s) on an intact human HGFpolypeptide or a fragment thereof as Ab1, Ab2, Ab7, Ab8, Ab9, Ab10,Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25, and Ab28.

In another embodiment of the invention, the anti-human HGF antibodywhich specifically binds to the same linear or conformational epitopeson an intact HGF polypeptide or fragment thereof that is (are)specifically bound by one of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8,Ab9, Ab10, Ab11, Ab12, Ab13 Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20,Ab21, Ab23, Ab24, Ab25, Ab26, Ab27 and Ab28 binds to HGF epitope(s)ascertained by epitopic mapping using overlapping linear peptidefragments which span the full length of the native human HGFpolypeptide.

The invention is also directed to an anti-HGF antibody that binds withthe same HGF epitope and/or competes with an anti-HGF antibody forbinding to HGF as an antibody or antibody fragment disclosed herein,including but not limited to an anti-HGF antibody selected from of Ab1,Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13 Ab14,Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab23, Ab24, Ab25, Ab26, Ab27and Ab28 or preferably one of Ab1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14,Ab19, Ab21, Ab23, Ab24, Ab25, or Ab28. In another embodiment, theinvention is also directed to an isolated anti-HGF antibody or antibodyfragment comprising one or more of the CDRs contained in the V_(H)polypeptide of an anti-HGF antibody selected from of Ab1, Ab2, Ab3, Ab4,Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13 Ab14, Ab15, Ab16, Ab17,Ab18, Ab19, Ab20, Ab21, Ab23, Ab24, Ab25, Ab26, Ab27 and Ab28 orpreferably one of as Ab1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14, Ab19,Ab21, Ab23, Ab24, Ab25, and Ab28.

In one embodiment of the invention, the anti-human HGF antibodycomprises at least 2 complementarity determining regions (CDRs) in eachthe variable light and the variable heavy regions which are identical tothose contained in an anti-human HGF antibody selected from the groupconsisting of an anti-HGF antibody selected from of Ab1, Ab2, Ab3, Ab4,Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13 Ab14, Ab15, Ab16, Ab17,Ab18, Ab19, Ab20, Ab21, Ab23, Ab24, Ab25, Ab26, Ab27 and Ab28 orpreferably one of Ab1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21,Ab23, Ab24, Ab25, and Ab28.

In a preferred embodiment, the anti-human HGF antibody discussed abovecomprises at least 2 complementarity determining regions (CDRs) in eachthe variable light and the variable heavy regions which are identical tothose contained in an anti-HGF antibody selected from of Ab1, Ab2, Ab7,Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25, and Ab28. Inanother embodiment, all of the CDRs of the anti-human HGF antibodydiscussed above are identical to the CDRs contained in an anti-human HGFantibody selected from the group consisting of an anti-HGF antibodyselected from of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10,Ab11, Ab12, Ab13 Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab23,Ab24, Ab25, Ab26, Ab27 and Ab28 or preferably one of as Ab1, Ab2, Ab7,Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25, and Ab28. In apreferred embodiment of the invention, all of the CDRs of the anti-humanHGF antibody discussed above are identical to the CDRs contained in ofAb1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25,or Ab28 or preferably one of Ab1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14,Ab19, Ab21, Ab23, Ab24, Ab25, and Ab28.

The invention further contemplates that the one or more anti-human HGFantibodies discussed above are aglycosylated; that contain an Fc regionthat has been modified to alter effector function, half-life,proteolysis, and/or glycosylation; are human, humanized, single chain orchimeric; and are a humanized antibody derived from a rabbit (parent)anti-human HGF antibody.

The invention further contemplates one or more anti-human HGF antibodieswherein the framework regions (FRs) in the variable light region and thevariable heavy regions of said antibody respectively are human FRs whichare unmodified or which have been modified by the substitution of atmost 2 or 3 human FR residues in the variable light or heavy chainregion with the corresponding FR residues of the parent rabbit antibody,and wherein said human FRs have been derived from human variable heavyand light chain antibody sequences which have been selected from alibrary of human germline antibody sequences based on their high levelof homology to the corresponding rabbit variable heavy or light chainregions relative to other human germline antibody sequences contained inthe library.

In one embodiment of the invention, the anti-human HGF antibody orfragment specifically binds to HGF expressing human cells and/or tocirculating soluble HGF molecules in vivo, including HGF expressed on orby human cells in a patient with a disease associated with cells thatexpress HGF.

In another embodiment, the disease is selected from cancers, includingovarian cancer, breast cancer, lung cancer (small cell or non-smallcell), colon cancer, prostate cancer, pancreatic cancer, renal cancer,gastric cancer, liver cancer, head-and-neck tumors, melanoma, sarcomas,and brain tumors (e.g., glioblastomas), of children or adults;leukemias; lymphomas; macular degeneration; Alzheimer's disease; andmalarial infection. In a preferred embodiment, the disease is selectedfrom a cancer or macular degeneration. In a particularly preferredembodiment, the disease is a cancer such as ovarian cancer, breastcancer, lung cancer (small cell or non-small cell), colon cancer,prostate cancer, pancreatic cancer, renal cancer, gastric cancer, livercancer, head-and-neck tumors, melanoma, sarcomas, and brain tumors(e.g., glioblastomas), of children or adults; leukemias; lymphomas oranother cancer.

The invention further contemplates anti-human HGF antibodies orfragments directly or indirectly attached to a detectable label ortherapeutic agent.

The invention also contemplates one or more nucleic acid sequences whichresult in the expression of an anti-human HGF antibody or antibodyfragment as set forth above, including those comprising, oralternatively consisting of, yeast or human preferred codons. Theinvention also contemplates vectors (including plasmids or recombinantviral vectors) comprising said nucleic acid sequence(s). The inventionalso contemplates host cells or recombinant host cells expressing atleast one of the antibodies set forth above, including a mammalian,yeast, bacterial, and insect cells. In a preferred embodiment, the hostcell is a yeast cell. In a further preferred embodiment, the yeast cellis a diploidal yeast cell. In a more preferred embodiment, the yeastcell is a Pichia yeast.

The invention also contemplates a method of treatment comprisingadministering to a patient with a disease or condition associated withHGF expressing cells a therapeutically effective amount of at least oneanti-human HGF antibody or fragment described herein. The invention alsocontemplates that the treatment method may involve the administration oftwo or more anti-HGF antibodies or fragments thereof and disclosedherein. If more than one antibody is administered to the patient, themultiple antibodies may be administered simultaneously or concurrently,or may be staggered in their administration. The diseases that may betreated are presented in the non-limiting list set forth above andelsewhere herein. In a preferred embodiment, the disease is selectedfrom a cancer or macular degeneration. In a particularly preferredembodiment, the disease is a cancer. In another embodiment the treatmentfurther includes the administration of another therapeutic agent orregimen selected from chemotherapy, radiotherapy, cytokineadministration or gene therapy.

In a non-limiting embodiment of the invention, the other therapeuticagent or regimen includes Taxol (paclitaxel) or its derivatives,platinum compounds such as carboplatin or cisplatin, anthrocyclines suchas doxorubicin, alkylating agents such as cyclophosphamide,anti-metabolites such as 5-fluorouracil, or etoposide. In addition,other therapeutic agents may be used in combination with the subjectanti-HGF antibodies and fragments, or other agents or methods used totreat cancer or other conditions wherein the use of an HGF antagonist istherapeutically beneficial.

For example, the other agent may be radiation, chemotherapy, anotheranti-angiogenic agent, an anti-proliferative agent. Other agents whichmay be used in association with the subject anti-HGF antibodies andfragments are disclosed infra Preferred examples include EGFR inhibitorssuch as a nucleoside analogue; or an inhibitor of platelet-derivedgrowth factor receptor (PDGFR), vascular endothelial growth factorreceptor (VEGFR), c-KIT kinase, or FMS-like tyrosine kinase 3 (FLT3).Such EGFR antagonist may function by binding to EGFR and competitivelyblocking binding of EGF or activation by EGF, for example the anti-EGFRmAbs cetuximab and panitumumab, or by inhibiting the tyrosine kinaseactivity of EGFR, for example erlotinib and gefitinib. More generally,downstream signaling pathways that may be inhibited by the second agentin the invention include the RAS-RAF-MEK-APK pathway and the P13K-AKTpathway. Many other signaling pathways and their inhibitors are wellknown to those skilled in the art of cellular biology. The nucleosideanalogues include gemcitabine, methotrexate, 5-fluorouracil, cytosinearabinoside, behenoyl cytosine arabinoside, tegafur, UFT, and the like.The inhibitors of PDGFR, VEGFR, c-KIT kinase or FLT3 include sunitinib,sorafenib, motesanib, and the like.

Also, the subject anti-HGF antibodies and fragments may be used incombination with hedgehog inhibitors such as an inhibitor of theHedgehog (HH) signaling pathway (particularly the HH pathway in humans),e.g., an agent that inhibits the ability of an HH protein to stimulate acell via this pathway, also called an HH pathway inhibitor or simply HHinhibitor. Such an agent may bind to the one or more of the HHligands—Sonic Hedgehog (SHH), Indian Hedgehog (IHH) and Desert Hedgehog(DHH)—or to their Patched 1 (PTCH1) or Patched 2 (PTCH2) receptors or toa downstream mediator such as Smoothened (SMOH) or SuFu or Iguana (alsoknown as DZIP1), or to one or more of the transcription factors GLI1,GLI2, and GLI3 activated by the pathway. All of these hedgehog pathwayproteins are well known human proteins for which sequences are availablefrom UniProtKB/Swiss-Prot and similar databases. Insofar as a proteinhas more than one known form in a species due to natural allelicvariation between individuals, an inhibitor can bind to and inhibit any,or all, of such known allelic forms, and preferably binds to andinhibits the wildtype, most common or first published allelic faun.Exemplary sequences for human SHH, IHH and DHH are assignedUniProtKB/Swiss-Prot accession numbers Q15465, Q14623, 043323 andrespectively. Exemplary sequences for other human hedgehog pathwayproteins are: PTCH1 (Q13635), PTCH2 (Q9Y6C5), SMOH (Q99835), DZIP1(Q86YF9), SuFu (Q9UMX1), Gli1 (P08151), Gli2 (P10070), Gli3 (P10071).The agent may be a protein such as a mAb, preferably a chimeric,humanized or human mAb, which binds to one or more of the HH proteins orto PTCH1 (or PTCH2), or may be a small molecule (i.e., a compound havingrelatively low molecular weight, most often less than 500 or 600 or 1000kDa). Exemplary small molecule second agents are cyclopamine,KAAD-cyclopamine(3-Keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)cyclopamine),SANT1-4 (Chen et al., Proc. Natl. Acad. Sci. USA 2002, 99:14071-14076,), CUR61414 (Williams et al., PNAS 2003 100: 8 4616-4621)and HhAntag-691 (Romer et al., Cancer Cell. 2004; 6:229-240); JK814 Lee,ChemBioChem 2007, 8: 1916-1919). Other examples of HH antagonists aredescribed by WO/2004/020599 and Katoh, Cancer Biol Ther. 2005 4:1050-4,and U.S. Pat. No. 7,300,929.

Also, the subject anti-HGF antibodies and fragments may be used incombination with an agonist of PTEN, preferably human PTEN. As usedherein, an “agonist of PTEN” or “PTEN agonist” means an agent thatstimulates the expression of PTEN in a cell, or stimulates the activityof PTEN, or which can provide one or more of the functions of PTEN,e.g., in regulating the PI3K/Akt/mTOR pathway. For example, PTEN is ableto indirectly reduce the activity of mTOR (mammalian target ofrapamycin) by downregulating the activity of Akt An inhibitor of mTORdirectly reproduces this particular role of PTEN—reduction of mTORactivity—so such an inhibitor is considered herein to be a PTEN agonist.This type of PTEN agonist will replace some but not necessarily all thefunctions of the tumor suppressor PTEN in a cancer cell with mutated ordeleted PTEN, and may therefore cause the cell to revert to a morenormal, less malignant phenotype. Preferred PTEN agonists/mTORinhibitors for use in the invention include rapamycin (Rapamune™,sirolimus, ATC code L04AA10 commercially available from Wyeth) and itschemical analogues such as CCI-779 (temsirolimus, Anatomical TherapeuticChemical (ATC) code L01XE09, commercially available from Wyeth), RAD-001(everolimus, ATC code L04AA18. commercially available from Novartis) andAP-2357 (Granville et al., op. cit.). Many PTEN agonists are smallmolecules (i.e., a compound having relatively low molecular weight, mostoften less than 500 or 600 kDa, or about 1000 kDa in the case of amacrolide such as rapamycin). Other agonists include mAbs, and zincfinger proteins or nucleic acids encoding the same, engineered to bindto and activate transcription of PTEN (see, e.g., WO 00/00388). OtherPTEN agonists are described in US20070280918. Whereas proteins aretypically administered parenterally, e.g. intravenously, small moleculesmay be administered parenterally or orally. PTEN and mTOR (also known asFRAP1) are well known human proteins for which sequences are availablefrom UniProtKB/Swiss-Prot and similar databases. Insofar as a proteinhas more than one known form in a species due to natural allelicvariation between individuals, an inhibitor can bind to and inhibit any,or all, of such known allelic forms, and preferably binds to andinhibits the wildtype, most common or first published allelic form.Exemplary sequences for human PTEN and mTOR(FRAP1) are assignedUniProtKB/Swiss-Prot accession numbers P60484 and P42345. This isintended to be exemplary and not exhaustive of potential combinationtherapies involving the subject anti-HGF antibodies and fragments andanother active agent.

The invention further contemplates a method of in vivo imaging whichdetects the presence of cells which express HGF comprising administeringa diagnostically effective amount of at least one anti-human HGFantibody according to the invention, preferably of Ab1, Ab2, Ab7, Ab8,Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25, or Ab28. In oneembodiment, said administration further includes the administration of aradionuclide or fluorophore that facilitates detection of the antibodyat HGF expressing disease sites. In another embodiment of the invention,the method of in vivo imaging is used to detect HGF expressing tumors ormetastases, or tumors or metastases expressing HGF-R capable of bindingto HGF. In a further embodiment, the results of said in vivo imagingmethod are used to facilitate the design of an appropriate therapeuticregimen, including therapeutic regimens including radiotherapy,chemotherapy or a combination thereof.

Polynucleotides Encoding Anti-HGF Antibody Polypeptides

Antibody Ab1

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 1:

(SEQ ID NO: 11) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtgcctatgcaatgagctgggtccgccaggctccagagaaggggctggagtggatcgcagtcatttatgttattggtgccactgactacgcgagctgggcgaaaggccgattcaccatctccagaacctcgaccacggtggatctgagaatccccagtccgacaaccgaggacacggccacctatttctgtgccagagtttatgattctgtctggaatcactttaacttgtggggcccgggcaccctggtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 2:

(SEQ ID NO: 12) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtgcctatgcaatgagctgggtccgccaggctccagagaaggggctggagtggatcgcagtcatttatgttattggtgccactgactacgcgagctgggcgaaaggccgattcaccatctccagaacctcgaccacggtggatctgagaatccccagtccgacaaccgaggacacggccacctatttctgtgccagagtttatgattctgtctggaatcactttaacttgtggggcccgggcaccctggtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 10:

(SEQ ID NO: 20) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO: 21:

(SEQ ID NO: 31) gcctatgatatgacccagactccagcctctgtggaggtagctgtggggggcacagtcaccatcaagtgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctaccaggcatctaaactggcatctggggtcccatcgcggttcaaaggcagtggatctgggacagagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactattgtcaacaggcttatagtgttagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 22:

(SEQ ID NO: 32) gcctatgatatgacccagactccagcctctgtggaggtagctgtggggggcacagtcaccatcaagtgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctaccaggcatctaaactggcatctggggtcccatcgcggttcaaaggcagtggatctgggacagagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactattgtcaacaggcttatagtgttagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 30:acggtggctgcaccatctgtettcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt (SEQ IDNO: 40).

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 14; SEQ ID NO: 16; and SEQ ID NO: 18, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 1 orthe variable heavy chain sequence of SEQ ID NO: 2, and/or one or more ofthe polynucleotide sequences of SEQ ID NO: 34; SEQ ID NO: 36; and SEQ IDNO: 38, which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the light chain sequence of SEQ IDNO: 21 or the variable light chain sequence of SEQ ID NO: 22, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 13; SEQ ID NO: 15; SEQ ID NO: 17; and SEQ ID NO: 19, whichcorrespond to polynucleotides encoding the framework regions (FRs orconstant regions) of the heavy chain sequence of SEQ ID NO: 1 or thevariable heavy chain sequence of SEQ ID NO: 2, and/or one or more of thepolynucleotide sequences of SEQ ID NO: 33; SEQ ID NO: 35; SEQ ID NO: 37;and SEQ ID NO: 39, which correspond to the framework regions (FRs orconstant regions) of the light chain sequence of SEQ ID NO: 21 or thevariable light chain sequence of SEQ ID NO: 22, or combinations of thesepolynucleotide sequences. In another embodiment of the invention, thepolynucleotides encoding the antibodies of the invention or fragmentsthereof comprise, or alternatively consist of, combinations of one ormore of the FRs, the variable heavy chain and variable light chainsequences, and the heavy chain and light chain sequences set forthabove, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 11 encoding the heavy chain sequence of SEQ IDNO: 1; the polynucleotide SEQ ID NO: 12 encoding the variable heavychain sequence of SEQ ID NO: 2; the polynucleotide SEQ ID NO: 31encoding the light chain sequence of SEQ ID NO: 21; the polynucleotideSEQ ID NO: 32 encoding the variable light chain sequence of SEQ ID NO:22; polynucleotides encoding the complementarity-determining regions(SEQ ID NO: 14; SEQ ID NO: 16; and SEQ ID NO: 18) of the heavy chainsequence of SEQ ID NO: 1 or the variable heavy chain sequence of SEQ IDNO: 2; polynucleotides encoding the complementarity-determining regions(SEQ ID NO: 34; SEQ ID NO: 36; and SEQ ID NO: 38) of the light chainsequence of SEQ ID NO: 21 or the variable light chain sequence of SEQ IDNO: 22; polynucleotides encoding the framework regions (SEQ ID NO: 13;SEQ ID NO: 15; SEQ ID NO: 17; and SEQ ID NO: 19) of the heavy chainsequence of SEQ ID NO: 1 or the variable heavy chain sequence of SEQ IDNO: 2; and polynucleotides encoding the framework regions (SEQ ID NO:33; SEQ ID NO: 35; SEQ ID NO: 37; and SEQ ID NO: 39) of the light chainsequence of SEQ ID NO: 21 or the variable light chain sequence of SEQ IDNO: 22.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab1, the polynucleotidesencoding the full length Ab1 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 11 encoding the heavy chain sequenceof SEQ ID NO: 1 and the polynucleotide SEQ ID NO: 31 encoding the lightchain sequence of SEQ ID NO: 21.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab1 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab1 or Fab fragments thereofmay be produced via expression of Ab1 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab2

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 41:

(SEQ ID NO: 51) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtgcctatgcaatgagctgggtccgtcaggctccagggaaggggctggagtgggtcgcagtcatctatgttattggtgccactgactacgcgagcagtgcgaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctgtctggaatcacttcaacttgtggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 42:

(SEQ ID NO: 52) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtgcctatgcaatgagctgggtccgtcaggctccagggaaggggctggagtgggtcgcagtcatctatgttattggtgccactgactacgcgagcagtgcgaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctgtctggaatcacttcaacttgtggggccaagggaccctcgtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 50:

(SEQ ID NO: 60) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO: 61:

(SEQ ID NO: 71) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatcaggcatctaaactggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttagtaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 62:

(SEQ ID NO: 72) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatcaggcatctaaactggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttagtaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 70:

(SEQ ID NO: 80) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 54; SEQ ID NO: 56; and SEQ ID NO: 58, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 41or the variable heavy chain sequence of SEQ ID NO: 42, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 74; SEQ ID NO: 76;and SEQ ID NO: 78, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 61 or the variable light chain sequence of SEQ ID NO: 62, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 53; SEQ ID NO: 55; SEQ ID NO: 57; and SEQ ID NO: 59, whichcorrespond to polynucleotides encoding the framework regions (FRs orconstant regions) of the heavy chain sequence of SEQ ID NO: 41 or thevariable heavy chain sequence of SEQ ID NO: 42, and/or one or more ofthe polynucleotide sequences of SEQ ID NO: 73; SEQ ID NO: 75; SEQ ID NO:77; and SEQ ID NO: 79, which correspond to the framework regions (FRs orconstant regions) of the light chain sequence of SEQ ID NO: 61 or thevariable light chain sequence of SEQ ID NO: 62, or combinations of thesepolynucleotide sequences. In another embodiment of the invention, thepolynucleotides encoding the antibodies of the invention or fragmentsthereof comprise, or alternatively consist of, combinations of one ormore of the FRs, the variable heavy chain and variable light chainsequences, and the heavy chain and light chain sequences set forthabove, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 51 encoding the heavy chain sequence of SEQ IDNO: 41; the polynucleotide SEQ ID NO: 52 encoding the variable heavychain sequence of SEQ ID NO: 42; the polynucleotide SEQ ID NO: 71encoding the light chain sequence of SEQ ID NO: 61; the polynucleotideSEQ ID NO: 72 encoding the variable light chain sequence of SEQ ID NO:62; polynucleotides encoding the complementarity-determining regions(SEQ ID NO: 54; SEQ ID NO: 56; and SEQ ID NO: 58) of the heavy chainsequence of SEQ ID NO: 41 or the variable heavy chain sequence of SEQ IDNO: 42; polynucleotides encoding the complementarity-determining regions(SEQ ID NO: 74; SEQ ID NO: 76; and SEQ ID NO: 78) of the light chainsequence of SEQ ID NO: 61 or the variable light chain sequence of SEQ IDNO: 62; polynucleotides encoding the framework regions (SEQ ID NO: 53;SEQ ID NO: 55; SEQ ID NO: 57; and SEQ ID NO: 59) of the heavy chainsequence of SEQ ID NO: 41 or the variable heavy chain sequence of SEQ IDNO: 42; and polynucleotides encoding the framework regions (SEQ ID NO:73; SEQ ID NO: 75; SEQ ID NO: 77; and SEQ ID NO: 79) of the light chainsequence of SEQ ID NO: 61 or the variable light chain sequence of SEQ IDNO: 62.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab2, the polynucleotidesencoding the full length Ab2 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 51 encoding the heavy chain sequenceof SEQ ID NO: 41 and the polynucleotide SEQ ID NO: 71 encoding the lightchain sequence of SEQ ID NO: 61.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab2 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab2 or Fab fragments thereofmay be produced via expression of Ab2 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab3

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 81:

(SEQ ID NO: 91) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccttgacactcacctgcacagtctctggactcaccattagtagctactacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaaccattaatcctggtgctaacacatacttcgcgagctgggcaaaaggccgattcaccatctccagaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacatatttctgtgccagagagggggatagtaatgactggggtgtctttgacttgtggggccagggcaccctggtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 82:

(SEQ ID NO: 92) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccttgacactcacctgcacagtctctggactcaccattagtagctactacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaaccattaatcctggtgctaacacatacttcgcgagctgggcaaaaggccgattcaccatctccagaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacatatttctgtgccagagagggggatagtaatgactggggtgtctttgacttgtggggccagggcaccctggtcaccgtctcgag c.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 90:

(SEQ ID NO: 100) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:101:

(SEQ ID NO: 111) gcctatgatatgacccagactccagcctctgtagagatagctgtgggaggcacagtcaccatcaggtgccaggccagtgaggacattgaaagctatttagcctggtatcagcagaaaccagggcagcctcccaaactcctgatctacagggcatccgatctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacagactacactctcaccatcagcggcgtggagtgtgacgatgctgccacttactactgtcaacagggttatactatcgataatgttgataatactttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 102:

(SEQ ID NO: 112) gcctatgatatgacccagactccagcctctgtagagatagctgtgggaggcacagtcaccatcaggtgccaggccagtgaggacattgaaagctatttagcctggtatcagcagaaaccagggcagcctcccaaactcctgatctacagggcatccgatctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacagactacactctcaccatcagcggcgtggagtgtgacgatgctgccacttactactgtcaacagggttatactatcgataatgttgataatactttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 110:

(SEQ ID NO: 120) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 94; SEQ ID NO: 96; and SEQ ID NO: 98, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 81or the variable heavy chain sequence of SEQ ID NO: 82, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 114; SEQ ID NO: 116;and SEQ ID NO: 118, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 101 or the variable light chain sequence of SEQ ID NO: 102,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 93; SEQ ID NO: 95; SEQ ID NO: 97; and SEQ ID NO: 99, whichcorrespond to polynucleotides encoding the framework regions (FRs orconstant regions) of the heavy chain sequence of SEQ ID NO: 81 or thevariable heavy chain sequence of SEQ ID NO: 82, and/or one or more ofthe polynucleotide sequences of SEQ ID NO: 113; SEQ ID NO: 115; SEQ IDNO: 117; and SEQ ID NO: 119, which correspond to the framework regions(FRs or constant regions) of the light chain sequence of SEQ ID NO: 101or the variable light chain sequence of SEQ ID NO: 102, or combinationsof these polynucleotide sequences. In another embodiment of theinvention, the polynucleotides encoding the antibodies of the inventionor fragments thereof comprise, or alternatively consist of, combinationsof one or more of the FRs, the variable heavy chain and variable lightchain sequences, and the heavy chain and light chain sequences set forthabove, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 91 encoding the heavy chain sequence of SEQ IDNO: 81; the polynucleotide SEQ ID NO: 92 encoding the variable heavychain sequence of SEQ ID NO: 82; the polynucleotide SEQ ID NO: 111encoding the light chain sequence of SEQ ID NO: 101; the polynucleotideSEQ ID NO: 112 encoding the variable light chain sequence of SEQ ID NO:102; polynucleotides encoding the complementarity-determining regions(SEQ ID NO: 94; SEQ ID NO: 96; and SEQ ID NO: 98) of the heavy chainsequence of SEQ ID NO: 81 or the variable heavy chain sequence of SEQ IDNO: 82; polynucleotides encoding the complementarity-determining regions(SEQ ID NO: 114; SEQ ID NO: 116; and SEQ ID NO: 118) of the light chainsequence of SEQ ID NO: 101 or the variable light chain sequence of SEQID NO: 102; polynucleotides encoding the framework regions (SEQ ID NO:93; SEQ ID NO: 95; SEQ ID NO: 97; and SEQ ID NO: 99) of the heavy chainsequence of SEQ ID NO: 81 or the variable heavy chain sequence of SEQ IDNO: 82; and polynucleotides encoding the framework regions (SEQ ID NO:113; SEQ ID NO: 115; SEQ ID NO: 117; and SEQ ID NO: 119) of the lightchain sequence of SEQ ID NO: 101 or the variable light chain sequence ofSEQ ID NO: 102.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab3, the polynucleotidesencoding the full length Ab3 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 91 encoding the heavy chain sequenceof SEQ ID NO: 81 and the polynucleotide SEQ ID NO: 111 encoding thelight chain sequence of SEQ ID NO: 101.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab3 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab3 or Fab fragments thereofmay be produced via expression of Ab3 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab4

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 121:

(SEQ ID NO: 131) cagtcgctggaggagtctgggggacgcttggtccagcctgggacacccctgacactctcctgtacagcctctggactcaccattagtagctactacatgagctgggtccgtcaggctccagggaaggggctggagtgggtcggaaccatcaatcctggtgctaacacatacttcgcgagctctgcaaaaggccgattcaccatctccagatcctcgaccaccctggatcttaagatgaccagcccgacagctgaggacactgctacatattactgtgctagagagggggatagtaatgactggggtgtctttgacttgtggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 122:

(SEQ ID NO: 132) cagtcgctggaggagtctgggggacgcttggtccagcctgggacacccctgacactctcctgtacagcctctggactcaccattagtagctactacatgagctgggtccgtcaggctccagggaaggggctggagtgggtcggaaccatcaatcctggtgctaacacatacttcgcgagctctgcaaaaggccgattcaccatctccagatcctcgaccaccctggatcttaagatgaccagcccgacagctgaggacactgctacatattactgtgctagagagggggatagtaatgactggggtgtctttgacttgtggggccaagggaccctcgtcaccgtctcgag c.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 130:

(SEQ ID NO: 140) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:141:

(SEQ ID NO: 151) gcctatgatatgacccagtctccagcctccgtggaggcagccgtaggaggcacagtcaccatcaggtgtcaggccagtgaggacattgaaagctacttagcctggtatcagcagaaaccagggcagcctcctaagctcctgatctatagggcatccgatctggcatctggggtctcatcaaggttcaaaggcagtggatctgggacagattacactctcaccatcagcggcctggagcctgaagatgctgcaacttactattgtcaacagggttatactatcgataatgttgacaatactttcggcggaggaaccaaggtggaaatcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 142:

(SEQ ID NO: 152) gcctatgatatgacccagtctccagcctccgtggaggcagccgtaggaggcacagtcaccatcaggtgtcaggccagtgaggacattgaaagctacttagcctggtatcagcagaaaccagggcagcctcctaagctcctgatctatagggcatccgatctggcatctggggtctcatcaaggttcaaaggcagtggatctgggacagattacactctcaccatcagcggcctggagcctgaagatgctgcaacttactattgtcaacagggttatactatcgataatgttgacaatactttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 150:

(SEQ ID NO: 160) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 134; SEQ ID NO: 136; and SEQ ID NO: 138, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 121or the variable heavy chain sequence of SEQ ID NO: 122, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 154; SEQ ID NO: 156;and SEQ ID NO: 158, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 141 or the variable light chain sequence of SEQ ID NO: 142,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 133; SEQ ID NO: 135; SEQ ID NO: 137; and SEQ ID NO: 139,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 121 orthe variable heavy chain sequence of SEQ ID NO: 122, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 153; SEQ ID NO: 155; SEQID NO: 157; and SEQ ID NO: 159, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 141 or the variable light chain sequence of SEQ ID NO: 142, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 131 encoding the heavy chain sequence of SEQID NO: 121; the polynucleotide SEQ ID NO: 132 encoding the variableheavy chain sequence of SEQ ID NO: 122; the polynucleotide SEQ ID NO:151 encoding the light chain sequence of SEQ ID NO: 141; thepolynucleotide SEQ ID NO: 152 encoding the variable light chain sequenceof SEQ ID NO: 142; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 134; SEQ ID NO: 136; andSEQ ID NO: 138) of the heavy chain sequence of SEQ ID NO: 121 or thevariable heavy chain sequence of SEQ ID NO: 122; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 154; SEQ IDNO: 156; and SEQ ID NO: 158) of the light chain sequence of SEQ ID NO:141 or the variable light chain sequence of SEQ ID NO: 142;polynucleotides encoding the framework regions (SEQ ID NO: 133; SEQ IDNO: 135; SEQ ID NO: 137; and SEQ ID NO: 139) of the heavy chain sequenceof SEQ ID NO: 121 or the variable heavy chain sequence of SEQ ID NO:122; and polynucleotides encoding the framework regions (SEQ ID NO: 153;SEQ ID NO: 155; SEQ ID NO: 157; and SEQ ID NO: 159) of the light chainsequence of SEQ ID NO: 141 or the variable light chain sequence of SEQID NO: 142.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab4, the polynucleotidesencoding the full length Ab4 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 131 encoding the heavy chain sequenceof SEQ ID NO: 121 and the polynucleotide SEQ ID NO: 151 encoding thelight chain sequence of SEQ ID NO: 141.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab4 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab4 or Fab fragments thereofmay be produced via expression of Ab4 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab5

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 161:

(SEQ ID NO: 171) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcaataattatgcagtgggctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttaccttagtggtaacacagactacgcgaactgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccaggaaatttgatacgggatatgacatctggggcccaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 162:

(SEQ ID NO: 172) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcaataattatgcagtgggctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttaccttagtggtaacacagactacgcgaactgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccaggaaatttgatacgggatatgacatctggggcccaggcaccctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 170:

(SEQ ID NO: 180) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:181:

(SEQ ID NO: 191) gcctatgatatgacccagactccagcctctatggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagtacctacttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctatgatgcatccgatctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgacgatgctgccacttactactgtcaacaggattggagtgatagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 182:

(SEQ ID NO: 192) gcctatgatatgacccagactccagcctctatggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagtacctacttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctatgatgcatccgatctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgacgatgctgccacttactactgtcaacaggattggagtgatagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 190:

(SEQ ID NO: 200) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 174; SEQ ID NO: 176; and SEQ ID NO: 178, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 161or the variable heavy chain sequence of SEQ ID NO: 162, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 194; SEQ ID NO: 196;and SEQ ID NO: 198, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 181 or the variable light chain sequence of SEQ ID NO: 182,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 173; SEQ ID NO: 175; SEQ ID NO: 177; and SEQ ID NO: 179,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 161 orthe variable heavy chain sequence of SEQ ID NO: 162, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 193; SEQ ID NO: 195; SEQID NO: 197; and SEQ ID NO: 199, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 181 or the variable light chain sequence of SEQ ID NO: 182, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 171 encoding the heavy chain sequence of SEQID NO: 161; the polynucleotide SEQ ID NO: 172 encoding the variableheavy chain sequence of SEQ ID NO: 162; the polynucleotide SEQ ID NO:191 encoding the light chain sequence of SEQ ID NO: 181; thepolynucleotide SEQ ID NO: 192 encoding the variable light chain sequenceof SEQ ID NO: 182; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 174; SEQ ID NO: 176; andSEQ ID NO: 178) of the heavy chain sequence of SEQ ID NO: 161 or thevariable heavy chain sequence of SEQ ID NO: 162; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 194; SEQ IDNO: 196; and SEQ ID NO: 198) of the light chain sequence of SEQ ID NO:181 or the variable light chain sequence of SEQ ID NO: 182;polynucleotides encoding the framework regions (SEQ ID NO: 173; SEQ IDNO: 175; SEQ ID NO: 177; and SEQ ID NO: 179) of the heavy chain sequenceof SEQ ID NO: 161 or the variable heavy chain sequence of SEQ ID NO:162; and polynucleotides encoding the framework regions (SEQ ID NO: 193;SEQ ID NO: 195; SEQ ID NO: 197; and SEQ ID NO: 199) of the light chainsequence of SEQ ID NO: 181 or the variable light chain sequence of SEQID NO: 182.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab5, the polynucleotidesencoding the full length Ab5 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 171 encoding the heavy chain sequenceof SEQ ID NO: 161 and the polynucleotide SEQ ID NO: 191 encoding thelight chain sequence of SEQ ID NO: 181.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab5 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab5 or Fab fragments thereofmay be produced via expression of Ab5 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab6

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 201:

(SEQ ID NO: 211) cagtcggtggaggagtccgggggtcgcctggtcatgcctgggacacccctgacactcacctgcaccgtctctggattctccctcagtagcaatgcaataagctgggtccgccaggctccagagaaggggctggaatggatcggagtcatttatgttattggtgtcactgactacgcgagctgggcgcaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatccccagtccgacaaccgaggacacggccacctatttctgtgccagagtttatgattctggctggaatcactttaacttgtggggcccgggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 202:

(SEQ ID NO: 212) cagtcggtggaggagtccgggggtcgcctggtcatgcctgggacacccctgacactcacctgcaccgtctctggattctccctcagtagcaatgcaataagctgggtccgccaggctccagagaaggggctggaatggatcggagtcatttatgttattggtgtcactgactacgcgagctgggcgcaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatccccagtccgacaaccgaggacacggccacctatttctgtgccagagtttatgattctggctggaatcactttaacttgtggggcccgggcaccctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 210:

(SEQ ID NO: 220) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:221:

(SEQ ID NO: 231) gctgacattgtgatgacccagactccatcctccgtggaggcagctgtgggaggcacagtcaccatcaagtgccaggccagtgagaacatttataggttattggcctggtatcagcagaaaccagggcagcgtcccaagctcctgatctattctgcatccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcaaaactattattatagtagtaggagtagttatgatacatataatgttttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagctt caacaggggagagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 222:

(SEQ ID NO: 232) gctgacattgtgatgacccagactccatcctccgtggaggcagctgtgggaggcacagtcaccatcaagtgccaggccagtgagaacatttataggttattggcctggtatcagcagaaaccagggcagcgtcccaagctcctgatctattctgcatccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcaaaactattattatagtagtaggagtagttatgatacatataatgttttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 230:

(SEQ ID NO: 240) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 201or the variable heavy chain sequence of SEQ ID NO: 202, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 234; SEQ ID NO: 236;and SEQ ID NO: 238, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 221 or the variable light chain sequence of SEQ ID NO: 222,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 213; SEQ ID NO: 215; SEQ ID NO: 217; and SEQ ID NO: 219,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 201 orthe variable heavy chain sequence of SEQ ID NO: 202, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 233; SEQ ID NO: 235; SEQID NO: 237; and SEQ ID NO: 239, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 221 or the variable light chain sequence of SEQ ID NO: 222, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 211 encoding the heavy chain sequence of SEQID NO: 201; the polynucleotide SEQ ID NO: 212 encoding the variableheavy chain sequence of SEQ ID NO: 202; the polynucleotide SEQ ID NO:231 encoding the light chain sequence of SEQ ID NO: 221; thepolynucleotide SEQ ID NO: 232 encoding the variable light chain sequenceof SEQ ID NO: 222; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 214; SEQ ID NO: 216; andSEQ ID NO: 218) of the heavy chain sequence of SEQ ID NO: 201 or thevariable heavy chain sequence of SEQ ID NO: 202; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 234; SEQ IDNO: 236; and SEQ ID NO: 238) of the light chain sequence of SEQ ID NO:221 or the variable light chain sequence of SEQ ID NO: 222;polynucleotides encoding the framework regions (SEQ ID NO: 213; SEQ IDNO: 215; SEQ ID NO: 217; and SEQ ID NO: 219) of the heavy chain sequenceof SEQ ID NO: 201 or the variable heavy chain sequence of SEQ ID NO:202; and polynucleotides encoding the framework regions (SEQ ID NO: 233;SEQ ID NO: 235; SEQ ID NO: 237; and SEQ ID NO: 239) of the light chainsequence of SEQ ID NO: 221 or the variable light chain sequence of SEQID NO: 222.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab6, the polynucleotidesencoding the full length Ab6 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 211 encoding the heavy chain sequenceof SEQ ID NO: 201 and the polynucleotide SEQ ID NO: 231 encoding thelight chain sequence of SEQ ID NO: 221.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab6 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab6 or Fab fragments thereofmay be produced via expression of Ab6 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab7

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 241:

(SEQ ID NO: 251) cagtcggtggaggagtccgggggtcgcctggtcatgcctgggacacccctgacactcacctgcaccgtctctggattctccctcagtagcaatgcaataagctgggtccgccaggctccagagaaggggctggaatggatcggagtcatttatgttattggtgtcactgactacgcgagctgggcgcaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatccccagtccgacaaccgaggacacggccacctatttctgtgccagagtttatgattctggctggaatcactttaacttgtggggcccagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 242:

(SEQ ID NO: 252) cagtcggtggaggagtccgggggtcgcctggtcatgcctgggacacccctgacactcacctgcaccgtctctggattctccctcagtagcaatgcaataagctgggtccgccaggctccagagaaggggctggaatggatcggagtcatttatgttattggtgtcactgactacgcgagctgggcgcaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatccccagtccgacaaccgaggacacggccacctatttctgtgccagagtttatgattctggctggaatcactttaacttgtggggcccagggaccctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 250:

(SEQ ID NO: 260) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:261:

(SEQ ID NO: 271) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccagggcagcctccaaagctcctgatctacgaagcatccaaactggcatctggggtcccatcgcggttcagtggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacaggcttatagtgttgccaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 262:

(SEQ ID NO: 272) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccagggcagcctccaaagctcctgatctacgaagcatccaaactggcatctggggtcccatcgcggttcagtggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacaggcttatagtgttgccaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 270:

(SEQ ID NO: 280) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 254; SEQ ID NO: 256; and SEQ ID NO: 258, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 241or the variable heavy chain sequence of SEQ ID NO: 242, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 274; SEQ ID NO: 276;and SEQ ID NO: 278, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 261 or the variable light chain sequence of SEQ ID NO: 262,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 253; SEQ ID NO: 255; SEQ ID NO: 257; and SEQ ID NO: 259,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 241 orthe variable heavy chain sequence of SEQ ID NO: 242, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 273; SEQ ID NO: 275; SEQID NO: 277; and SEQ ID NO: 279, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 261 or the variable light chain sequence of SEQ ID NO: 262, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 251 encoding the heavy chain sequence of SEQID NO: 241; the polynucleotide SEQ ID NO: 252 encoding the variableheavy chain sequence of SEQ ID NO: 242; the polynucleotide SEQ ID NO:271 encoding the light chain sequence of SEQ ID NO: 261; thepolynucleotide SEQ ID NO: 272 encoding the variable light chain sequenceof SEQ ID NO: 262; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 254; SEQ ID NO: 256; andSEQ ID NO: 258) of the heavy chain sequence of SEQ ID NO: 241 or thevariable heavy chain sequence of SEQ ID NO: 242; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 274; SEQ IDNO: 276; and SEQ ID NO: 278) of the light chain sequence of SEQ ID NO:261 or the variable light chain sequence of SEQ ID NO: 262;polynucleotides encoding the framework regions (SEQ ID NO: 253; SEQ IDNO: 255; SEQ ID NO: 257; and SEQ ID NO: 259) of the heavy chain sequenceof SEQ ID NO: 241 or the variable heavy chain sequence of SEQ ID NO:242; and polynucleotides encoding the framework regions (SEQ ID NO: 273;SEQ ID NO: 275; SEQ ID NO: 277; and SEQ ID NO: 279) of the light chainsequence of SEQ ID NO: 261 or the variable light chain sequence of SEQID NO: 262.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab7, the polynucleotidesencoding the full length Ab7 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 251 encoding the heavy chain sequenceof SEQ ID NO: 241 and the polynucleotide SEQ ID NO: 271 encoding thelight chain sequence of SEQ ID NO: 261.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab7 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab7 or Fab fragments thereofmay be produced via expression of Ab7 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab8

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 281:

(SEQ ID NO: 291) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatgcaataagctgggtccgtcaggctccagggaaggggctggagtgggtcggagtcatttatgttattggtgtcactgactacgcgagctctgcgcaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctggctggaatcactttaacttgtggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 282:

(SEQ ID NO: 292) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatgcaataagctgggtccgtcaggctccagggaaggggctggagtgggtcggagtcatttatgttattggtgtcactgactacgcgagctctgcgcaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctggctggaatcactttaacttgtggggccaagggaccctcgtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 290:

(SEQ ID NO: 300) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:301:

(SEQ ID NO: 311) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatgaagcatccaaactggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttgccaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 302:

(SEQ ID NO: 312) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatgaagcatccaaactggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttgccaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 310:

(SEQ ID NO: 320) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 294; SEQ ID NO: 296; and SEQ ID NO: 298, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 281or the variable heavy chain sequence of SEQ ID NO: 282, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 314; SEQ ID NO: 316;and SEQ ID NO: 318, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 301 or the variable light chain sequence of SEQ ID NO: 302,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 293; SEQ ID NO: 295; SEQ ID NO: 297; and SEQ ID NO: 299,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 281 orthe variable heavy chain sequence of SEQ ID NO: 282, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 313; SEQ ID NO: 315; SEQID NO: 317; and SEQ ID NO: 319, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 301 or the variable light chain sequence of SEQ ID NO: 302, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 291 encoding the heavy chain sequence of SEQID NO: 281; the polynucleotide SEQ ID NO: 292 encoding the variableheavy chain sequence of SEQ ID NO: 282; the polynucleotide SEQ ID NO:311 encoding the light chain sequence of SEQ ID NO: 301; thepolynucleotide SEQ ID NO: 312 encoding the variable light chain sequenceof SEQ ID NO: 302; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 294; SEQ ID NO: 296; andSEQ ID NO: 298) of the heavy chain sequence of SEQ ID NO: 281 or thevariable heavy chain sequence of SEQ ID NO: 282; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 314; SEQ IDNO: 316; and SEQ ID NO: 318) of the light chain sequence of SEQ ID NO:301 or the variable light chain sequence of SEQ ID NO: 302;polynucleotides encoding the framework regions (SEQ ID NO: 293; SEQ IDNO: 295; SEQ ID NO: 297; and SEQ ID NO: 299) of the heavy chain sequenceof SEQ ID NO: 281 or the variable heavy chain sequence of SEQ ID NO:282; and polynucleotides encoding the framework regions (SEQ ID NO: 313;SEQ ID NO: 315; SEQ ID NO: 317; and SEQ ID NO: 319) of the light chainsequence of SEQ ID NO: 301 or the variable light chain sequence of SEQID NO: 302.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab8, the polynucleotidesencoding the full length Ab8 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 291 encoding the heavy chain sequenceof SEQ ID NO: 281 and the polynucleotide SEQ ID NO: 311 encoding thelight chain sequence of SEQ ID NO: 301.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab8 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab8 or Fab fragments thereofmay be produced via expression of Ab8 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab9

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 321:

(SEQ ID NO: 331) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtgtctggaatcgacctcaatagcaatggaatgagctgggtccgccaggctccaggggaggggctggaatggatcggagccagtagtattgatgggaccacatactacaccaattgggcgaagggccgattcaccatctccaaaacctcgtcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtaccagaggggagtatgctggtgttgttggttcgaactactttgacttgtggggccagggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa a.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 322:

(SEQ ID NO: 332) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtgtctggaatcgacctcaatagcaatggaatgagctgggtccgccaggctccaggggaggggctggaatggatcggagccagtagtattgatgggaccacatactacaccaattgggcgaagggccgattcaccatctccaaaacctcgtcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtaccagaggggagtatgctggtgttgttggttcgaactactttgacttgtggggccagggcaccctcgtcac cgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 330:

(SEQ ID NO: 340) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:341:

(SEQ ID NO: 351) caagtgctgacccagactccaccctccgtgtctgcagttgtgggaggcacagtcaccatcaattgccagtccagtcagaggatttatagtaattggttatcttggtatcagcagaaaccagggcagactcccaagcccctgatctatgctgcatccagcctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcgacctggagtgtgacgatgctgccagttactactgtgcaggctattatagtggtcatatttattctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 342:

(SEQ ID NO: 352) caagtgctgacccagactccaccctccgtgtctgcagttgtgggaggcacagtcaccatcaattgccagtccagtcagaggatttatagtaattggttatcttggtatcagcagaaaccagggcagactcccaagcccctgatctatgctgcatccagcctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcgacctggagtgtgacgatgctgccagttactactgtgcaggctattatagtggtcatatttattctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 350:

(SEQ ID NO: 360) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 334; SEQ ID NO: 336; and SEQ ID NO: 338, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 321or the variable heavy chain sequence of SEQ ID NO: 322, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 354; SEQ ID NO: 356;and SEQ ID NO: 358, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 341 or the variable light chain sequence of SEQ ID NO: 342,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 333; SEQ ID NO: 335; SEQ ID NO: 337; and SEQ ID NO: 339,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 321 orthe variable heavy chain sequence of SEQ ID NO: 322, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 353; SEQ ID NO: 355; SEQID NO: 357; and SEQ ID NO: 359, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 341 or the variable light chain sequence of SEQ ID NO: 342, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 331 encoding the heavy chain sequence of SEQID NO: 321; the polynucleotide SEQ ID NO: 332 encoding the variableheavy chain sequence of SEQ ID NO: 322; the polynucleotide SEQ ID NO:351 encoding the light chain sequence of SEQ ID NO: 341; thepolynucleotide SEQ ID NO: 352 encoding the variable light chain sequenceof SEQ ID NO: 342; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 334; SEQ ID NO: 336; andSEQ ID NO: 338) of the heavy chain sequence of SEQ ID NO: 321 or thevariable heavy chain sequence of SEQ ID NO: 322; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 354; SEQ IDNO: 356; and SEQ ID NO: 358) of the light chain sequence of SEQ ID NO:341 or the variable light chain sequence of SEQ ID NO: 342;polynucleotides encoding the framework regions (SEQ ID NO: 333; SEQ IDNO: 335; SEQ ID NO: 337; and SEQ ID NO: 339) of the heavy chain sequenceof SEQ ID NO: 321 or the variable heavy chain sequence of SEQ ID NO:322; and polynucleotides encoding the framework regions (SEQ ID NO: 353;SEQ ID NO: 355; SEQ ID NO: 357; and SEQ ID NO: 359) of the light chainsequence of SEQ ID NO: 341 or the variable light chain sequence of SEQID NO: 342.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab9, the polynucleotidesencoding the full length Ab9 antibody comprise, or alternatively consistof, the polynucleotide SEQ ID NO: 331 encoding the heavy chain sequenceof SEQ ID NO: 321 and the polynucleotide SEQ ID NO: 351 encoding thelight chain sequence of SEQ ID NO: 341.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab9 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab9 or Fab fragments thereofmay be produced via expression of Ab9 polynucleotides in mammalian cellssuch as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systemssuch as yeast cells (for example diploid yeast such as diploid Pichia)and other yeast strains. Suitable Pichia species include, but are notlimited to, Pichia pastoris.

Antibody Ab10

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 361:

(SEQ ID NO: 371) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatggaatgagctgggtccgtcaggctccagggaaggggctggagtgggtcggagccagtagtattgatgggaccacatactacaccaattctgcgaagggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagaggggagtatgctggtgttgttggttcgaactactttgacttgtggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccg ggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 362:

(SEQ ID NO: 372) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatggaatgagctgggtccgtcaggctccagggaaggggctggagtgggtcggagccagtagtattgatgggaccacatactacaccaattctgcgaagggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagaggggagtatgctggtgttgttggttcgaactactttgacttgtggggccaagggaccct cgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 370:

(SEQ ID NO: 380) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:381:

(SEQ ID NO: 391) gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggagacagagtcaccatcacttgtcagtccagtcagaggatctatagtaattggttatcttggtatcagcagaaaccagggaaagcccctaagctcctgatctatgctgcatccagcctggcatctggggtcccatcaaggttcagcggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagattttgcaacttactattgtgcaggctactatagtggtcatatctattctttcggcggaggaaccaaggtggaaatcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 382:

(SEQ ID NO: 392) gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggagacagagtcaccatcacttgtcagtccagtcagaggatctatagtaattggttatcttggtatcagcagaaaccagggaaagcccctaagctcctgatctatgctgcatccagcctggcatctggggtcccatcaaggttcagcggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagattttgcaacttactattgtgcaggctactatagtggtcatatctattctttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 390:

(SEQ ID NO: 400) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 374; SEQ ID NO: 376; and SEQ ID NO: 378, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 361or the variable heavy chain sequence of SEQ ID NO: 362, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 394; SEQ ID NO: 396;and SEQ ID NO: 398, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 381 or the variable light chain sequence of SEQ ID NO: 382,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 373; SEQ ID NO: 375; SEQ ID NO: 377; and SEQ ID NO: 379,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 361 orthe variable heavy chain sequence of SEQ ID NO: 362, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 393; SEQ ID NO: 395; SEQID NO: 397; and SEQ ID NO: 399, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 381 or the variable light chain sequence of SEQ ID NO: 382, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 371 encoding the heavy chain sequence of SEQID NO: 361; the polynucleotide SEQ ID NO: 372 encoding the variableheavy chain sequence of SEQ ID NO: 362; the polynucleotide SEQ ID NO:391 encoding the light chain sequence of SEQ ID NO: 381; thepolynucleotide SEQ ID NO: 392 encoding the variable light chain sequenceof SEQ ID NO: 382; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 374; SEQ ID NO: 376; andSEQ ID NO: 378) of the heavy chain sequence of SEQ ID NO: 361 or thevariable heavy chain sequence of SEQ ID NO: 362; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 394; SEQ IDNO: 396; and SEQ ID NO: 398) of the light chain sequence of SEQ ID NO:381 or the variable light chain sequence of SEQ ID NO: 382;polynucleotides encoding the framework regions (SEQ ID NO: 373; SEQ IDNO: 375; SEQ ID NO: 377; and SEQ ID NO: 379) of the heavy chain sequenceof SEQ ID NO: 361 or the variable heavy chain sequence of SEQ ID NO:362; and polynucleotides encoding the framework regions (SEQ ID NO: 393;SEQ ID NO: 395; SEQ ID NO: 397; and SEQ ID NO: 399) of the light chainsequence of SEQ ID NO: 381 or the variable light chain sequence of SEQID NO: 382.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab10, the polynucleotidesencoding the full length Ab10 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 371 encoding the heavy chainsequence of SEQ ID NO: 361 and the polynucleotide SEQ ID NO: 391encoding the light chain sequence of SEQ ID NO: 381.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab10 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab10 or Fab fragments thereofmay be produced via expression of Ab10 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab11

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 401:

(SEQ ID NO: 411) cagtcaatggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtgactatgcgttgagctgggtccgccaggctccagggaaggggctggaatggatcggaatgattagtagtggtgacaacacatactacgcgagctgggcgaaaggccgattcaccatctccaaagcctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagagataaagatgctagtagtggtggttatttggtccttgacctattggatgtccccgacggcatggacctctggggcccaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 402:

(SEQ ID NO: 412) cagtcaatggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtgactatgcgttgagctgggtccgccaggctccagggaaggggctggaatggatcggaatgattagtagtggtgacaacacatactacgcgagctgggcgaaaggccgattcaccatctccaaagcctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagagataaagatgctagtagtggtggttatttggtccttgacctattggatgtccccgacggcatggacctctggggcccaggcaccctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 410:

(SEQ ID NO: 420) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:421:

(SEQ ID NO: 431) gccgtgctgacccagacaccatcgcccgtgtctgcagctgtgggaggcacagtcaccatcaagtgccagtccagtcagagtgtttataataacaacctcttatcctggtatcagcagaaaccagggcagcctcccaagctcctgatctggggtgcatcctatctgccatctggggtcccagataggttcagcggcagtggatctgggacacagttcactctcaccatcagcggcgtgcagtgtgacgatgctgccacttactactgtctaggcggttatgatggtgatgctgatacatataatactttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggg agagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 422:

(SEQ ID NO: 432) gccgtgctgacccagacaccatcgcccgtgtctgcagctgtgggaggcacagtcaccatcaagtgccagtccagtcagagtgtttataataacaacctcttatcctggtatcagcagaaaccagggcagcctcccaagctcctgatctggggtgcatcctatctgccatctggggtcccagataggttcagcggcagtggatctgggacacagttcactctcaccatcagcggcgtgcagtgtgacgatgctgccacttactactgtctaggcggttatgatggtgatgctgatacatataatactttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 430:

(SEQ ID NO: 440) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 414; SEQ ID NO: 416; and SEQ ID NO: 418, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 401or the variable heavy chain sequence of SEQ ID NO: 402, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 434; SEQ ID NO: 436;and SEQ ID NO: 438, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 421 or the variable light chain sequence of SEQ ID NO: 422,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 413; SEQ ID NO: 415; SEQ ID NO: 417; and SEQ ID NO: 419,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 401 orthe variable heavy chain sequence of SEQ ID NO: 402, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 433; SEQ ID NO: 435; SEQID NO: 437; and SEQ ID NO: 439, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 421 or the variable light chain sequence of SEQ ID NO: 422, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 411 encoding the heavy chain sequence of SEQID NO: 401; the polynucleotide SEQ ID NO: 412 encoding the variableheavy chain sequence of SEQ ID NO: 402; the polynucleotide SEQ ID NO:431 encoding the light chain sequence of SEQ ID NO: 421; thepolynucleotide SEQ ID NO: 432 encoding the variable light chain sequenceof SEQ ID NO: 422; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 414; SEQ ID NO: 416; andSEQ ID NO: 418) of the heavy chain sequence of SEQ ID NO: 401 or thevariable heavy chain sequence of SEQ ID NO: 402; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 434; SEQ IDNO: 436; and SEQ ID NO: 438) of the light chain sequence of SEQ ID NO:421 or the variable light chain sequence of SEQ ID NO: 422;polynucleotides encoding the framework regions (SEQ ID NO: 413; SEQ IDNO: 415; SEQ ID NO: 417; and SEQ ID NO: 419) of the heavy chain sequenceof SEQ ID NO: 401 or the variable heavy chain sequence of SEQ ID NO:402; and polynucleotides encoding the framework regions (SEQ ID NO: 433;SEQ ID NO: 435; SEQ ID NO: 437; and SEQ ID NO: 439) of the light chainsequence of SEQ ID NO: 421 or the variable light chain sequence of SEQID NO: 422.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab11, the polynucleotidesencoding the full length Ab11 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 411 encoding the heavy chainsequence of SEQ ID NO: 401 and the polynucleotide SEQ ID NO: 431encoding the light chain sequence of SEQ ID NO: 421.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab11 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab11 or Fab fragments thereofmay be produced via expression of Ab11 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab12

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 441:

(SEQ ID NO: 451) cagtcgctggaggagtccgggggtcgcctggtaacgcctggaggatccctgacactcacctgcacagtctctggaatcgacctcagtagcaatgcaataagctgggtccgccaggctccagagaaggggctggagtggatcgcagtcatttatgttgttggtgccactgactacgcgagctgggcgaaaggccgattcaccatctccagaacctcgaccacggtggatctgaaaatgaccagtctgacaaccgaggacacggccacctatttctgtgccagagtttatgattctggctggaatcactttaacttgtggggcccaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 442:

(SEQ ID NO: 452) cagtcgctggaggagtccgggggtcgcctggtaacgcctggaggatccctgacactcacctgcacagtctctggaatcgacctcagtagcaatgcaataagctgggtccgccaggctccagagaaggggctggagtggatcgcagtcatttatgttgttggtgccactgactacgcgagctgggcgaaaggccgattcaccatctccagaacctcgaccacggtggatctgaaaatgaccagtctgacaaccgaggacacggccacctatttctgtgccagagtttatgattctggctggaatcactttaacttgtggggcccaggcaccctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 450:

(SEQ ID NO: 460) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:461:

(SEQ ID NO: 471) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggtcagtcagagcattagtagttggttatcctggtatcagaagaaaccagggcagcgtcccaagctcctgatctacagggcatccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacagagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacaggcttatagtgttagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 462:

(SEQ ID NO: 472) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggtcagtcagagcattagtagttggttatcctggtatcagaagaaaccagggcagcgtcccaagctcctgatctacagggcatccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacagagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacaggcttatagtgttagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 470:

(SEQ ID NO: 480) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 454; SEQ ID NO: 456; and SEQ ID NO: 458, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 441or the variable heavy chain sequence of SEQ ID NO: 442, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 474; SEQ ID NO: 476;and SEQ ID NO: 478, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 461 or the variable light chain sequence of SEQ ID NO: 462,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 453; SEQ ID NO: 455; SEQ ID NO: 457; and SEQ ID NO: 459,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 441 orthe variable heavy chain sequence of SEQ ID NO: 442, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 473; SEQ ID NO: 475; SEQID NO: 477; and SEQ ID NO: 479, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 461 or the variable light chain sequence of SEQ ID NO: 462, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 451 encoding the heavy chain sequence of SEQID NO: 441; the polynucleotide SEQ ID NO: 452 encoding the variableheavy chain sequence of SEQ ID NO: 442; the polynucleotide SEQ ID NO:471 encoding the light chain sequence of SEQ ID NO: 461; thepolynucleotide SEQ ID NO: 472 encoding the variable light chain sequenceof SEQ ID NO: 462; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 454; SEQ ID NO: 456; andSEQ ID NO: 458) of the heavy chain sequence of SEQ ID NO: 441 or thevariable heavy chain sequence of SEQ ID NO: 442; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 474; SEQ IDNO: 476; and SEQ ID NO: 478) of the light chain sequence of SEQ ID NO:461 or the variable light chain sequence of SEQ ID NO: 462;polynucleotides encoding the framework regions (SEQ ID NO: 453; SEQ IDNO: 455; SEQ ID NO: 457; and SEQ ID NO: 459) of the heavy chain sequenceof SEQ ID NO: 441 or the variable heavy chain sequence of SEQ ID NO:442; and polynucleotides encoding the framework regions (SEQ ID NO: 473;SEQ ID NO: 475; SEQ ID NO: 477; and SEQ ID NO: 479) of the light chainsequence of SEQ ID NO: 461 or the variable light chain sequence of SEQID NO: 462.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab12, the polynucleotidesencoding the full length Ab12 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 451 encoding the heavy chainsequence of SEQ ID NO: 441 and the polynucleotide SEQ ID NO: 471encoding the light chain sequence of SEQ ID NO: 461.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab12 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab12 or Fab fragments thereofmay be produced via expression of Ab12 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab13

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 481:

(SEQ ID NO: 491) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatgcaataagctgggtccgtcaggctccagggaaggggctggagtgggtcgcagtcatctatgttgttggtgccactgactacgcgagcagtgcgaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctggctggaatcactttaacttgtggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 482:

(SEQ ID NO: 492) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatgcaataagctgggtccgtcaggctccagggaaggggctggagtgggtcgcagtcatctatgttgttggtgccactgactacgcgagcagtgcgaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctggctggaatcactttaacttgtggggccaagggaccctcgtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 490:

(SEQ ID NO: 500) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:501:

(SEQ ID NO: 511) gactatcagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggtcagtcagagcattagtagttggttatcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatagggcatccactctggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttagtaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 502:

(SEQ ID NO: 512) gactatcagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggtcagtcagagcattagtagttggttatcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatagggcatccactctggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttagtaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 510:

(SEQ ID NO: 520) acggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 494; SEQ ID NO: 496; and SEQ ID NO: 498, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 481or the variable heavy chain sequence of SEQ ID NO: 482, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 514; SEQ ID NO: 516;and SEQ ID NO: 518, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 501 or the variable light chain sequence of SEQ ID NO: 502,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 493; SEQ ID NO: 495; SEQ ID NO: 497; and SEQ ID NO: 499,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 481 orthe variable heavy chain sequence of SEQ ID NO: 482, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 513; SEQ ID NO: 515; SEQID NO: 517; and SEQ ID NO: 519, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 501 or the variable light chain sequence of SEQ ID NO: 502, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 491 encoding the heavy chain sequence of SEQID NO: 481; the polynucleotide SEQ ID NO: 492 encoding the variableheavy chain sequence of SEQ ID NO: 482; the polynucleotide SEQ ID NO:511 encoding the light chain sequence of SEQ ID NO: 501; thepolynucleotide SEQ ID NO: 512 encoding the variable light chain sequenceof SEQ ID NO: 502; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 494; SEQ ID NO: 496; andSEQ ID NO: 498) of the heavy chain sequence of SEQ ID NO: 481 or thevariable heavy chain sequence of SEQ ID NO: 482; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 514; SEQ IDNO: 516; and SEQ ID NO: 518) of the light chain sequence of SEQ ID NO:501 or the variable light chain sequence of SEQ ID NO: 502;polynucleotides encoding the framework regions (SEQ ID NO: 493; SEQ IDNO: 495; SEQ ID NO: 497; and SEQ ID NO: 499) of the heavy chain sequenceof SEQ ID NO: 481 or the variable heavy chain sequence of SEQ ID NO:482; and polynucleotides encoding the framework regions (SEQ ID NO: 513;SEQ ID NO: 515; SEQ ID NO: 517; and SEQ ID NO: 519) of the light chainsequence of SEQ ID NO: 501 or the variable light chain sequence of SEQID NO: 502.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab13, the polynucleotidesencoding the full length Ab13 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 491 encoding the heavy chainsequence of SEQ ID NO: 481 and the polynucleotide SEQ ID NO: 511encoding the light chain sequence of SEQ ID NO: 501.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab13 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab13 or Fab fragments thereofmay be produced via expression of Ab13 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab14

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 521:

(SEQ ID NO: 531) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtaactacgcaatgacctgggtccgccaggctccagggaaggggctggaatggatcggagtcattagttttggtggtaacacatactacgcgaactgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagatgggatgctgaaaacaatgagattcttaacttgtggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 522:

(SEQ ID NO: 532) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtaactacgcaatgacctgggtccgccaggctccagggaaggggctggaatggatcggagtcattagttttggtggtaacacatactacgcgaactgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagatgggatgctgaaaacaatgagattcttaacttgtggggccaagggaccctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 530:

(SEQ ID NO: 540) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:541:

(SEQ ID NO: 551) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattgaaagctatttagcctggtatcagcagaaatcagggcagcctcccaagctcctgatctacagggcttccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggaatgtgccgatgctgccacttactactgtcaacagggtgatgcttggagtaatgttgataatgttttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 542:

(SEQ ID NO: 552) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattgaaagctatttagcctggtatcagcagaaatcagggcagcctcccaagctcctgatctacagggcttccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggaatgtgccgatgctgccacttactactgtcaacagggtgatgcttggagtaatgttgataatgttttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 550:

(SEQ ID NO: 560) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 534; SEQ ID NO: 536; and SEQ ID NO: 538, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 521or the variable heavy chain sequence of SEQ ID NO: 522, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 554; SEQ ID NO: 556;and SEQ ID NO: 558, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 541 or the variable light chain sequence of SEQ ID NO: 542,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 533; SEQ ID NO: 535; SEQ ID NO: 537; and SEQ ID NO: 539,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 521 orthe variable heavy chain sequence of SEQ ID NO: 522, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 553; SEQ ID NO: 555; SEQID NO: 557; and SEQ ID NO: 559, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 541 or the variable light chain sequence of SEQ ID NO: 542, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 531 encoding the heavy chain sequence of SEQID NO: 521; the polynucleotide SEQ ID NO: 532 encoding the variableheavy chain sequence of SEQ ID NO: 522; the polynucleotide SEQ ID NO:551 encoding the light chain sequence of SEQ ID NO: 541; thepolynucleotide SEQ ID NO: 552 encoding the variable light chain sequenceof SEQ ID NO: 542; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 534; SEQ ID NO: 536; andSEQ ID NO: 538) of the heavy chain sequence of SEQ ID NO: 521 or thevariable heavy chain sequence of SEQ ID NO: 522; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 554; SEQ IDNO: 556; and SEQ ID NO: 558) of the light chain sequence of SEQ ID NO:541 or the variable light chain sequence of SEQ ID NO: 542;polynucleotides encoding the framework regions (SEQ ID NO: 533; SEQ IDNO: 535; SEQ ID NO: 537; and SEQ ID NO: 539) of the heavy chain sequenceof SEQ ID NO: 521 or the variable heavy chain sequence of SEQ ID NO:522; and polynucleotides encoding the framework regions (SEQ ID NO: 553;SEQ ID NO: 555; SEQ ID NO: 557; and SEQ ID NO: 559) of the light chainsequence of SEQ ID NO: 541 or the variable light chain sequence of SEQID NO: 542.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab14, the polynucleotidesencoding the full length Ab14 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 531 encoding the heavy chainsequence of SEQ ID NO: 521 and the polynucleotide SEQ ID NO: 551encoding the light chain sequence of SEQ ID NO: 541.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab14 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab14 or Fab fragments thereofmay be produced via expression of Ab14 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab15

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 561:

(SEQ ID NO: 571) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtaactacgcaatgacctgggtccgccaggctccagggaaggggctggaatggatcggagtcattagttttggtggtaacacatactacgcgaactgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagatgggatgctgaaaacaatgagattcttaacttgtggggcccagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 562:

(SEQ ID NO: 572) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtaactacgcaatgacctgggtccgccaggctccagggaaggggctggaatggatcggagtcattagttttggtggtaacacatactacgcgaactgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagatgggatgctgaaaacaatgagattcttaacttgtggggcccagggaccctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 570:

(SEQ ID NO: 580) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:581:

(SEQ ID NO: 591) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattagtagctacttagcctggtatcagcagaaatcagggcagcctcccaagctcctgatctacagggcttccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacagggtgatgcttggagtaatgttgataatgttttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 582:

(SEQ ID NO: 592) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattagtagctacttagcctggtatcagcagaaatcagggcagcctcccaagctcctgatctacagggcttccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacagggtgatgcttggagtaatgttgataatgttttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 590:

(SEQ ID NO: 600) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 574; SEQ ID NO: 576; and SEQ ID NO: 578, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 561or the variable heavy chain sequence of SEQ ID NO: 562, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 594; SEQ ID NO: 596;and SEQ ID NO: 598, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 581 or the variable light chain sequence of SEQ ID NO: 582,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 573; SEQ ID NO: 575; SEQ ID NO: 577; and SEQ ID NO: 579,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 561 orthe variable heavy chain sequence of SEQ ID NO: 562, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 593; SEQ ID NO: 595; SEQID NO: 597; and SEQ ID NO: 599, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 581 or the variable light chain sequence of SEQ ID NO: 582, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 571 encoding the heavy chain sequence of SEQID NO: 561; the polynucleotide SEQ ID NO: 572 encoding the variableheavy chain sequence of SEQ ID NO: 562; the polynucleotide SEQ ID NO:591 encoding the light chain sequence of SEQ ID NO: 581; thepolynucleotide SEQ ID NO: 592 encoding the variable light chain sequenceof SEQ ID NO: 582; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 574; SEQ ID NO: 576; andSEQ ID NO: 578) of the heavy chain sequence of SEQ ID NO: 561 or thevariable heavy chain sequence of SEQ ID NO: 562; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 594; SEQ IDNO: 596; and SEQ ID NO: 598) of the light chain sequence of SEQ ID NO:581 or the variable light chain sequence of SEQ ID NO: 582;polynucleotides encoding the framework regions (SEQ ID NO: 573; SEQ IDNO: 575; SEQ ID NO: 577; and SEQ ID NO: 579) of the heavy chain sequenceof SEQ ID NO: 561 or the variable heavy chain sequence of SEQ ID NO:562; and polynucleotides encoding the framework regions (SEQ ID NO: 593;SEQ ID NO: 595; SEQ ID NO: 597; and SEQ ID NO: 599) of the light chainsequence of SEQ ID NO: 581 or the variable light chain sequence of SEQID NO: 582.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab15, the polynucleotidesencoding the full length Ab15 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 571 encoding the heavy chainsequence of SEQ ID NO: 561 and the polynucleotide SEQ ID NO: 591encoding the light chain sequence of SEQ ID NO: 581.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab15 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab15 or Fab fragments thereofmay be produced via expression of Ab15 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab16

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 601:

(SEQ ID NO: 611) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggaatcgacctcagtaattatgcaatgggctgggtccgccaggctccagggaaggggctggaatacatcggaatgattggtgttaatggtagggcatggtacgcgacttgggcgaaaggccgattcaccatctccaagacctcgcccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagattgattgacgagcgttcaacttatagttatgtttttgacttgtggggccaaggcaccctggtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 602:

(SEQ ID NO: 612) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggaatcgacctcagtaattatgcaatgggctgggtccgccaggctccagggaaggggctggaatacatcggaatgattggtgttaatggtagggcatggtacgcgacttgggcgaaaggccgattcaccatctccaagacctcgcccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagattgattgacgagcgttcaacttatagttatgtttttgacttgtggggccaaggcaccctggtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 610:

(SEQ ID NO: 620) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:621:

(SEQ ID NO: 631) caagtgctgacccagactccatcccctgtgtctgcagctgtgggaggcacagtcaccatcaactgccagggcagtcagagtctttataataacaacgccttttcctggtatcagcagaaaccagggcagcctcccaagctcctgatctatgatgcttccactctggcgtctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagtggcgtgcagtgtgcagatgctgccacttactactgtcaaggcgaatttagttgtggtgatgttgattgtattgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggg agagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 622:

(SEQ ID NO: 632) caagtgctgacccagactccatcccctgtgtctgcagctgtgggaggcacagtcaccatcaactgccagggcagtcagagtctttataataacaacgccttttcctggtatcagcagaaaccagggcagcctcccaagctcctgatctatgatgcttccactctggcgtctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagtggcgtgcagtgtgcagatgctgccacttactactgtcaaggcgaatttagttgtggtgatgttgattgtattgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 630:

(SEQ ID NO: 640) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 614; SEQ ID NO: 616; and SEQ ID NO: 618, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 601or the variable heavy chain sequence of SEQ ID NO: 602, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 634; SEQ ID NO: 636;and SEQ ID NO: 638, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 621 or the variable light chain sequence of SEQ ID NO: 622,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 613; SEQ ID NO: 615; SEQ ID NO: 617; and SEQ ID NO: 619,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 601 orthe variable heavy chain sequence of SEQ ID NO: 602, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 633; SEQ ID NO: 635; SEQID NO: 637; and SEQ ID NO: 639, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 621 or the variable light chain sequence of SEQ ID NO: 622, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 611 encoding the heavy chain sequence of SEQID NO: 601; the polynucleotide SEQ ID NO: 612 encoding the variableheavy chain sequence of SEQ ID NO: 602; the polynucleotide SEQ ID NO:631 encoding the light chain sequence of SEQ ID NO: 621; thepolynucleotide SEQ ID NO: 632 encoding the variable light chain sequenceof SEQ ID NO: 622; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 614; SEQ ID NO: 616; andSEQ ID NO: 618) of the heavy chain sequence of SEQ ID NO: 601 or thevariable heavy chain sequence of SEQ ID NO: 602; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 634; SEQ IDNO: 636; and SEQ ID NO: 638) of the light chain sequence of SEQ ID NO:621 or the variable light chain sequence of SEQ ID NO: 622;polynucleotides encoding the framework regions (SEQ ID NO: 613; SEQ IDNO: 615; SEQ ID NO: 617; and SEQ ID NO: 619) of the heavy chain sequenceof SEQ ID NO: 601 or the variable heavy chain sequence of SEQ ID NO:602; and polynucleotides encoding the framework regions (SEQ ID NO: 633;SEQ ID NO: 635; SEQ ID NO: 637; and SEQ ID NO: 639) of the light chainsequence of SEQ ID NO: 621 or the variable light chain sequence of SEQID NO: 622.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab16, the polynucleotidesencoding the full length Ab16 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 611 encoding the heavy chainsequence of SEQ ID NO: 601 and the polynucleotide SEQ ID NO: 631encoding the light chain sequence of SEQ ID NO: 621.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab16 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab16 or Fab fragments thereofmay be produced via expression of Ab16 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab17

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 641:

(SEQ ID NO: 651) cagtcggtggaggagtccgggggtcgcctggtcccgcctgggacacccctgacactcacctgcacagtctctggaatcgacctcagtagctatgcaatgggctgggtccgccaggctccagggaaggggctggaatacatcggaatgattgatgttagtggtagcacgtactacgcggactgggcgaaaggccgactcaccatctccaaaaccccgaccacggtggatctggaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagattgattgacgagcgttcaacttatagttatgcttttgacttgtggggccaaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 642:

(SEQ ID NO: 652) cagtcggtggaggagtccgggggtcgcctggtcccgcctgggacacccctgacactcacctgcacagtctctggaatcgacctcagtagctatgcaatgggctgggtccgccaggctccagggaaggggctggaatacatcggaatgattgatgttagtggtagcacgtactacgcggactgggcgaaaggccgactcaccatctccaaaaccccgaccacggtggatctggaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagattgattgacgagcgttcaacttatagttatgcttttgacttgtggggccaaggcaccctcgtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 650:

(SEQ ID NO: 660) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:661:

(SEQ ID NO: 671) caagtgctgacccagactccatcccctgtgtctgcagctgtgggaggcacagtcaccatcaactgccaggccagtcagagtttttataataacggcgccttttcctggtatcagcagaaaccagggcagcctcccaagctcctgatctacgatgcatccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtacagtgtggagatgctgccacttactactgtcaaggcgaatttagttgtggtagtgctgattgtgttgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggg agagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 662:

(SEQ ID NO: 672) caagtgctgacccagactccatcccctgtgtctgcagctgtgggaggcacagtcaccatcaactgccaggccagtcagagtttttataataacggcgccttttcctggtatcagcagaaaccagggcagcctcccaagctcctgatctacgatgcatccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtacagtgtggagatgctgccacttactactgtcaaggcgaatttagttgtggtagtgctgattgtgttgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 670:

(SEQ ID NO: 680) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 654; SEQ ID NO: 656; and SEQ ID NO: 658, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 641or the variable heavy chain sequence of SEQ ID NO: 642, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 674; SEQ ID NO: 676;and SEQ ID NO: 678, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 661 or the variable light chain sequence of SEQ ID NO: 662,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 653; SEQ ID NO: 655; SEQ ID NO: 657; and SEQ ID NO: 659,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 641 orthe variable heavy chain sequence of SEQ ID NO: 642, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 673; SEQ ID NO: 675; SEQID NO: 677; and SEQ ID NO: 679, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 661 or the variable light chain sequence of SEQ ID NO: 662, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 651 encoding the heavy chain sequence of SEQID NO: 641; the polynucleotide SEQ ID NO: 652 encoding the variableheavy chain sequence of SEQ ID NO: 642; the polynucleotide SEQ ID NO:671 encoding the light chain sequence of SEQ ID NO: 661; thepolynucleotide SEQ ID NO: 672 encoding the variable light chain sequenceof SEQ ID NO: 662; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 654; SEQ ID NO: 656; andSEQ ID NO: 658) of the heavy chain sequence of SEQ ID NO: 641 or thevariable heavy chain sequence of SEQ ID NO: 642; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 674; SEQ IDNO: 676; and SEQ ID NO: 678) of the light chain sequence of SEQ ID NO:661 or the variable light chain sequence of SEQ ID NO: 662;polynucleotides encoding the framework regions (SEQ ID NO: 653; SEQ IDNO: 655; SEQ ID NO: 657; and SEQ ID NO: 659) of the heavy chain sequenceof SEQ ID NO: 641 or the variable heavy chain sequence of SEQ ID NO:642; and polynucleotides encoding the framework regions (SEQ ID NO: 673;SEQ ID NO: 675; SEQ ID NO: 677; and SEQ ID NO: 679) of the light chainsequence of SEQ ID NO: 661 or the variable light chain sequence of SEQID NO: 662.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab17, the polynucleotidesencoding the full length Ab17 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 651 encoding the heavy chainsequence of SEQ ID NO: 641 and the polynucleotide SEQ ID NO: 671encoding the light chain sequence of SEQ ID NO: 661.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab17 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab17 or Fab fragments thereofmay be produced via expression of Ab17 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab18

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 681:

(SEQ ID NO: 691) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagcagctacgacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatgctggtagtgctagcacatggttcgcgagctgggtgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatgaccagtctgacaaccgaggacacggccacctatttctgtgccagagtgggttatagtggttatggttatgatgataatttggacatgtggggccaaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggta aa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 682:

(SEQ ID NO: 692) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagcagctacgacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatgctggtagtgctagcacatggttcgcgagctgggtgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatgaccagtctgacaaccgaggacacggccacctatttctgtgccagagtgggttatagtggttatggttatgatgataatttggacatgtggggccaaggcaccctcgtcac cgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 690:

(SEQ ID NO: 700) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:701:

(SEQ ID NO: 711) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagcactgcattagcctggtatcagcagaaaccagggcagcgtcccaagctcctgatctacgatgcatcgaaactggcatctggggtctcatcgcggttcaaaggcagtggatctggggcacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaccagggttatagtagtagtaatgttgataatactttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 702:

(SEQ ID NO: 712) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagcactgcattagcctggtatcagcagaaaccagggcagcgtcccaagctcctgatctacgatgcatcgaaactggcatctggggtctcatcgcggttcaaaggcagtggatctggggcacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaccagggttatagtagtagtaatgttgataatactttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 710:

(SEQ ID NO: 720) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 694; SEQ ID NO: 696; and SEQ ID NO: 698, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 681or the variable heavy chain sequence of SEQ ID NO: 682, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 714; SEQ ID NO: 716;and SEQ ID NO: 718, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 701 or the variable light chain sequence of SEQ ID NO: 702,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 693; SEQ ID NO: 695; SEQ ID NO: 697; and SEQ ID NO: 699,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 681 orthe variable heavy chain sequence of SEQ ID NO: 682, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 713; SEQ ID NO: 715; SEQID NO: 717; and SEQ ID NO: 719, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 701 or the variable light chain sequence of SEQ ID NO: 702, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 691 encoding the heavy chain sequence of SEQID NO: 681; the polynucleotide SEQ ID NO: 692 encoding the variableheavy chain sequence of SEQ ID NO: 682; the polynucleotide SEQ ID NO:711 encoding the light chain sequence of SEQ ID NO: 701; thepolynucleotide SEQ ID NO: 712 encoding the variable light chain sequenceof SEQ ID NO: 702; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 694; SEQ ID NO: 696; andSEQ ID NO: 698) of the heavy chain sequence of SEQ ID NO: 681 or thevariable heavy chain sequence of SEQ ID NO: 682; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 714; SEQ IDNO: 716; and SEQ ID NO: 718) of the light chain sequence of SEQ ID NO:701 or the variable light chain sequence of SEQ ID NO: 702;polynucleotides encoding the framework regions (SEQ ID NO: 693; SEQ IDNO: 695; SEQ ID NO: 697; and SEQ ID NO: 699) of the heavy chain sequenceof SEQ ID NO: 681 or the variable heavy chain sequence of SEQ ID NO:682; and polynucleotides encoding the framework regions (SEQ ID NO: 713;SEQ ID NO: 715; SEQ ID NO: 717; and SEQ ID NO: 719) of the light chainsequence of SEQ ID NO: 701 or the variable light chain sequence of SEQID NO: 702.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab18, the polynucleotidesencoding the full length Ab18 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 691 encoding the heavy chainsequence of SEQ ID NO: 681 and the polynucleotide SEQ ID NO: 711encoding the light chain sequence of SEQ ID NO: 701.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab18 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab18 or Fab fragments thereofmay be produced via expression of Ab18 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab19

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 721:

(SEQ ID NO: 731) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagtaattattggatgggctgggtccgccaggctccaggggaggggctggaatggatcggaaccattagttatgatggtaacacatactacgcgagctgggcaaaaggccgcttcaccatctcccgaacctcgaccacggtggatctgaaaatgaccagtctgacgaccgaggacacggccatctatttctgtgccacagtcaattatcctgattatagtactggtgcctttaacatctggggcccaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 722:

(SEQ ID NO: 732) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagtaattattggatgggctgggtccgccaggctccaggggaggggctggaatggatcggaaccattagttatgatggtaacacatactacgcgagctgggcaaaaggccgcttcaccatctcccgaacctcgaccacggtggatctgaaaatgaccagtctgacgaccgaggacacggccatctatttctgtgccacagtcaattatcctgattatagtactggtgcctttaacatctggggcccaggcaccctcgtcaccgtctc gagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 730:

(SEQ ID NO: 740) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:741:

(SEQ ID NO: 751) gatgttgtgatgacccagactccagcctccgtgtctgaacctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattgataactacttagcctggtatcagcagaaaccagggcagcgtcccaggctcctgatctattatacatccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacagagtacactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcaatttactgcttattatagtacttatattggagctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 742:

(SEQ ID NO: 752) gatgttgtgatgacccagactccagcctccgtgtctgaacctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattgataactacttagcctggtatcagcagaaaccagggcagcgtcccaggctcctgatctattatacatccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacagagtacactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcaatttactgcttattatagtacttatattggagctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 750:

(SEQ ID NO: 760) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 734; SEQ ID NO: 736; and SEQ ID NO: 738, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 721or the variable heavy chain sequence of SEQ ID NO: 722, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 754; SEQ ID NO: 756;and SEQ ID NO: 758, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 741 or the variable light chain sequence of SEQ ID NO: 742,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 733; SEQ ID NO: 735; SEQ ID NO: 737; and SEQ ID NO: 739,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 721 orthe variable heavy chain sequence of SEQ ID NO: 722, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 753; SEQ ID NO: 755; SEQID NO: 757; and SEQ ID NO: 759, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 741 or the variable light chain sequence of SEQ ID NO: 742, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 731 encoding the heavy chain sequence of SEQID NO: 721; the polynucleotide SEQ ID NO: 732 encoding the variableheavy chain sequence of SEQ ID NO: 722; the polynucleotide SEQ ID NO:751 encoding the light chain sequence of SEQ ID NO: 741; thepolynucleotide SEQ ID NO: 752 encoding the variable light chain sequenceof SEQ ID NO: 742; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 734; SEQ ID NO: 736; andSEQ ID NO: 738) of the heavy chain sequence of SEQ ID NO: 721 or thevariable heavy chain sequence of SEQ ID NO: 722; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 754; SEQ IDNO: 756; and SEQ ID NO: 758) of the light chain sequence of SEQ ID NO:741 or the variable light chain sequence of SEQ ID NO: 742;polynucleotides encoding the framework regions (SEQ ID NO: 733; SEQ IDNO: 735; SEQ ID NO: 737; and SEQ ID NO: 739) of the heavy chain sequenceof SEQ ID NO: 721 or the variable heavy chain sequence of SEQ ID NO:722; and polynucleotides encoding the framework regions (SEQ ID NO: 753;SEQ ID NO: 755; SEQ ID NO: 757; and SEQ ID NO: 759) of the light chainsequence of SEQ ID NO: 741 or the variable light chain sequence of SEQID NO: 742.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab19, the polynucleotidesencoding the full length Ab19 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 731 encoding the heavy chainsequence of SEQ ID NO: 721 and the polynucleotide SEQ ID NO: 751encoding the light chain sequence of SEQ ID NO: 741.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab19 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab19 or Fab fragments thereofmay be produced via expression of Ab19 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab20

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 761:

(SEQ ID NO: 771) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtaactattggatgggctgggtccgtcaggctccagggaaggggctggagtggatcggaaccattagttatgatggtaacacatactacgcgagcagcgcaaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctacagtcaattatcctgattatagtactggtgcctttaacatctggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt aaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 762:

(SEQ ID NO: 772) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtaactattggatgggctgggtccgtcaggctccagggaaggggctggagtggatcggaaccattagttatgatggtaacacatactacgcgagcagcgcaaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctacagtcaattatcctgattatagtactggtgcctttaacatctggggccaagggaccctcgt caccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 770:

(SEQ ID NO: 780) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:781:

(SEQ ID NO: 791) gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattgataactacttagcctggtatcagcagaaaccagggaaagttcctaagctcctgatctattatacatccactctggcatctggggtcccatctcgtttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagatgttgcaacttattactgtcaattcactgcttattatagtacttacattggagctttcggcggaggaaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 782:

(SEQ ID NO: 792) gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattgataactacttagcctggtatcagcagaaaccagggaaagttcctaagctcctgatctattatacatccactctggcatctggggtcccatctcgtttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagatgttgcaacttattactgtcaattcactgcttattatagtacttacattggagctttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 790:

(SEQ ID NO: 800) acggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 774; SEQ ID NO: 776; and SEQ ID NO: 778, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 761or the variable heavy chain sequence of SEQ ID NO: 762, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 794; SEQ ID NO: 796;and SEQ ID NO: 798, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 781 or the variable light chain sequence of SEQ ID NO: 782,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 773; SEQ ID NO: 775; SEQ ID NO: 777; and SEQ ID NO: 779,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 761 orthe variable heavy chain sequence of SEQ ID NO: 762, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 793; SEQ ID NO: 795; SEQID NO: 797; and SEQ ID NO: 799, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 781 or the variable light chain sequence of SEQ ID NO: 782, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 771 encoding the heavy chain sequence of SEQID NO: 761; the polynucleotide SEQ ID NO: 772 encoding the variableheavy chain sequence of SEQ ID NO: 762; the polynucleotide SEQ ID NO:791 encoding the light chain sequence of SEQ ID NO: 781; thepolynucleotide SEQ ID NO: 792 encoding the variable light chain sequenceof SEQ ID NO: 782; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 774; SEQ ID NO: 776; andSEQ ID NO: 778) of the heavy chain sequence of SEQ ID NO: 761 or thevariable heavy chain sequence of SEQ ID NO: 762; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 794; SEQ IDNO: 796; and SEQ ID NO: 798) of the light chain sequence of SEQ ID NO:781 or the variable light chain sequence of SEQ ID NO: 782;polynucleotides encoding the framework regions (SEQ ID NO: 773; SEQ IDNO: 775; SEQ ID NO: 777; and SEQ ID NO: 779) of the heavy chain sequenceof SEQ ID NO: 761 or the variable heavy chain sequence of SEQ ID NO:762; and polynucleotides encoding the framework regions (SEQ ID NO: 793;SEQ ID NO: 795; SEQ ID NO: 797; and SEQ ID NO: 799) of the light chainsequence of SEQ ID NO: 781 or the variable light chain sequence of SEQID NO: 782.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab20, the polynucleotidesencoding the full length Ab20 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 771 encoding the heavy chainsequence of SEQ ID NO: 761 and the polynucleotide SEQ ID NO: 791encoding the light chain sequence of SEQ ID NO: 781.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab20 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab20 or Fab fragments thereofmay be produced via expression of Ab20 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab21

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 801:

(SEQ ID NO: 811) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcaccgtctctggattctccctcagtacctactacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatgttagtggtatcacggactacgcgaggtgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatgaccagtctgacaaccgaggacacggccacctatttctgtgccagacatattgatagtagtggctgggatggactgggcatctggggccaaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 802:

(SEQ ID NO: 812) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcaccgtctctggattctccctcagtacctactacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatgttagtggtatcacggactacgcgaggtgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatgaccagtctgacaaccgaggacacggccacctatttctgtgccagacatattgatagtagtggctgggatggactgggcatctggggccaaggcaccctcgtcaccgtctcgag c.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 810:

(SEQ ID NO: 820) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:821:

(SEQ ID NO: 831) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattagtagctacttaaactggtatcagcagaaactagggcagcctcccaagctcctgatctacagggcatccactctgacatctggggtctcatcaaggttcaaaggcagtggatctgggacagagtacactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcagcagacttatggttatagtgatactgataattctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 822:

(SEQ ID NO: 832) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattagtagctacttaaactggtatcagcagaaactagggcagcctcccaagctcctgatctacagggcatccactctgacatctggggtctcatcaaggttcaaaggcagtggatctgggacagagtacactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcagcagacttatggttatagtgatactgataattctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 830:

(SEQ ID NO: 840) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 814; SEQ ID NO: 816; and SEQ ID NO: 818, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 801or the variable heavy chain sequence of SEQ ID NO: 802, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 834; SEQ ID NO: 836;and SEQ ID NO: 838, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 821 or the variable light chain sequence of SEQ ID NO: 822,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 813; SEQ ID NO: 815; SEQ ID NO: 817; and SEQ ID NO: 819,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 801 orthe variable heavy chain sequence of SEQ ID NO: 802, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 833; SEQ ID NO: 835; SEQID NO: 837; and SEQ ID NO: 839, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 821 or the variable light chain sequence of SEQ ID NO: 822, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 811 encoding the heavy chain sequence of SEQID NO: 801; the polynucleotide SEQ ID NO: 812 encoding the variableheavy chain sequence of SEQ ID NO: 802; the polynucleotide SEQ ID NO:831 encoding the light chain sequence of SEQ ID NO: 821; thepolynucleotide SEQ ID NO: 832 encoding the variable light chain sequenceof SEQ ID NO: 822; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 814; SEQ ID NO: 816; andSEQ ID NO: 818) of the heavy chain sequence of SEQ ID NO: 801 or thevariable heavy chain sequence of SEQ ID NO: 802; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 834; SEQ IDNO: 836; and SEQ ID NO: 838) of the light chain sequence of SEQ ID NO:821 or the variable light chain sequence of SEQ ID NO: 822;polynucleotides encoding the framework regions (SEQ ID NO: 813; SEQ IDNO: 815; SEQ ID NO: 817; and SEQ ID NO: 819) of the heavy chain sequenceof SEQ ID NO: 801 or the variable heavy chain sequence of SEQ ID NO:802; and polynucleotides encoding the framework regions (SEQ ID NO: 833;SEQ ID NO: 835; SEQ ID NO: 837; and SEQ ID NO: 839) of the light chainsequence of SEQ ID NO: 821 or the variable light chain sequence of SEQID NO: 822.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab21, the polynucleotidesencoding the full length Ab21 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 811 encoding the heavy chainsequence of SEQ ID NO: 801 and the polynucleotide SEQ ID NO: 831encoding the light chain sequence of SEQ ID NO: 821.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab21 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab21 or Fab fragments thereofmay be produced via expression of Ab21 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab23

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 841:

(SEQ ID NO: 851) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattcactatcggtcgctactacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatactcatggtgttaacccagactacgcgagctgggcgaaaggccgattcaccatctccagaccctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagagtgggtggttttaatgactactctgacatttggggcccaggcaccctggtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 842:

(SEQ ID NO: 852) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattcactatcggtcgctactacatgagctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatactcatggtgttaacccagactacgcgagctgggcgaaaggccgattcaccatctccagaccctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagagtgggtggttttaatgactactctgacatttggggcccaggcaccctggtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 850:

(SEQ ID NO: 860) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:861:

(SEQ ID NO: 871) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattagtacctacttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctacagggcatccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacagggttatagttatagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 862:

(SEQ ID NO: 872) gcctatgatatgacccagactccagcctctgtggaggtagctgtgggaggcacagtcaccatcaagtgccaggccagtgagagcattagtacctacttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctacagggcatccactctggcatctggggtctcatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcggcgtggagtgtgccgatgctgccacttactactgtcaacagggttatagttatagtaatgttgataatgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 870:

(SEQ ID NO: 880) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 854; SEQ ID NO: 856; and SEQ ID NO: 858, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 841or the variable heavy chain sequence of SEQ ID NO: 842, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 874; SEQ ID NO: 876;and SEQ ID NO: 878, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 861 or the variable light chain sequence of SEQ ID NO: 862,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 853; SEQ ID NO: 855; SEQ ID NO: 857; and SEQ ID NO: 859,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 841 orthe variable heavy chain sequence of SEQ ID NO: 842, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 873; SEQ ID NO: 875; SEQID NO: 877; and SEQ ID NO: 879, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 861 or the variable light chain sequence of SEQ ID NO: 862, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 851 encoding the heavy chain sequence of SEQID NO: 841; the polynucleotide SEQ ID NO: 852 encoding the variableheavy chain sequence of SEQ ID NO: 842; the polynucleotide SEQ ID NO:871 encoding the light chain sequence of SEQ ID NO: 861; thepolynucleotide SEQ ID NO: 872 encoding the variable light chain sequenceof SEQ ID NO: 862; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 854; SEQ ID NO: 856; andSEQ ID NO: 858) of the heavy chain sequence of SEQ ID NO: 841 or thevariable heavy chain sequence of SEQ ID NO: 842; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 874; SEQ IDNO: 876; and SEQ ID NO: 878) of the light chain sequence of SEQ ID NO:861 or the variable light chain sequence of SEQ ID NO: 862;polynucleotides encoding the framework regions (SEQ ID NO: 853; SEQ IDNO: 855; SEQ ID NO: 857; and SEQ ID NO: 859) of the heavy chain sequenceof SEQ ID NO: 841 or the variable heavy chain sequence of SEQ ID NO:842; and polynucleotides encoding the framework regions (SEQ ID NO: 873;SEQ ID NO: 875; SEQ ID NO: 877; and SEQ ID NO: 879) of the light chainsequence of SEQ ID NO: 861 or the variable light chain sequence of SEQID NO: 862.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab23, the polynucleotidesencoding the full length Ab23 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 851 encoding the heavy chainsequence of SEQ ID NO: 841 and the polynucleotide SEQ ID NO: 871encoding the light chain sequence of SEQ ID NO: 861.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab23 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab23 or Fab fragments thereofmay be produced via expression of Ab23 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab24

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 881:

(SEQ ID NO: 891) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcggtcgctactacatgagctgggtccgtcaggctccagggaaggggctggagtggatcggaatcatctatactcatggtgttaacccagactacgcgagcagcgcgaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtgggtggtttcaatgactactctgacatttggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 882:

(SEQ ID NO: 892) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcggtcgctactacatgagctgggtccgtcaggctccagggaaggggctggagtggatcggaatcatctatactcatggtgttaacccagactacgcgagcagcgcgaaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtgggtggtttcaatgactactctgacatttggggccaagggaccctcgtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 890:

(SEQ ID NO: 900) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:901:

(SEQ ID NO: 911) gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtgagagcattagtacctacttagcctggtatcagcagaaaccagggaaagttcctaagctcctgatctatagggcatccactctggcatctggggtcccatctcgtttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagatgttgcaacttattactgtcaacagggttatagttatagtaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 902:

(SEQ ID NO: 912) gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtgagagcattagtacctacttagcctggtatcagcagaaaccagggaaagttcctaagctcctgatctatagggcatccactctggcatctggggtcccatctcgtttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagatgttgcaacttattactgtcaacagggttatagttatagtaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 910:

(SEQ ID NO: 920) acggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 894; SEQ ID NO: 896; and SEQ ID NO: 898, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 881or the variable heavy chain sequence of SEQ ID NO: 882, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 914; SEQ ID NO: 916;and SEQ ID NO: 918, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 901 or the variable light chain sequence of SEQ ID NO: 902,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 893; SEQ ID NO: 895; SEQ ID NO: 897; and SEQ ID NO: 899,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 881 orthe variable heavy chain sequence of SEQ ID NO: 882, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 913; SEQ ID NO: 915; SEQID NO: 917; and SEQ ID NO: 919, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 901 or the variable light chain sequence of SEQ ID NO: 902, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 891 encoding the heavy chain sequence of SEQID NO: 881; the polynucleotide SEQ ID NO: 892 encoding the variableheavy chain sequence of SEQ ID NO: 882; the polynucleotide SEQ ID NO:911 encoding the light chain sequence of SEQ ID NO: 901; thepolynucleotide SEQ ID NO: 912 encoding the variable light chain sequenceof SEQ ID NO: 902; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 894; SEQ ID NO: 896; andSEQ ID NO: 898) of the heavy chain sequence of SEQ ID NO: 881 or thevariable heavy chain sequence of SEQ ID NO: 882; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 914; SEQ IDNO: 916; and SEQ ID NO: 918) of the light chain sequence of SEQ ID NO:901 or the variable light chain sequence of SEQ ID NO: 902;polynucleotides encoding the framework regions (SEQ ID NO: 893; SEQ IDNO: 895; SEQ ID NO: 897; and SEQ ID NO: 899) of the heavy chain sequenceof SEQ ID NO: 881 or the variable heavy chain sequence of SEQ ID NO:882; and polynucleotides encoding the framework regions (SEQ ID NO: 913;SEQ ID NO: 915; SEQ ID NO: 917; and SEQ ID NO: 919) of the light chainsequence of SEQ ID NO: 901 or the variable light chain sequence of SEQID NO: 902.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab24, the polynucleotidesencoding the full length Ab24 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 891 encoding the heavy chainsequence of SEQ ID NO: 881 and the polynucleotide SEQ ID NO: 911encoding the light chain sequence of SEQ ID NO: 901.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab24 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab24 or Fab fragments thereofmay be produced via expression of Ab24 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab25

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 921:

(SEQ ID NO: 931) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagtagctatgcaatgggctggttccgccaggctccagggaaggggctggagtggatcgcatacatttttgctagtggtagcacatactacgcgagctgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggagctgaaaatcaccagtctgacaaccgaggacacggccacctatttctgtgccagaggtagtggtgctcgttttttccccaactactttgccatctggggcccaggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 922:

(SEQ ID NO: 932) cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagtagctatgcaatgggctggttccgccaggctccagggaaggggctggagtggatcgcatacatttttgctagtggtagcacatactacgcgagctgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggagctgaaaatcaccagtctgacaaccgaggacacggccacctatttctgtgccagaggtagtggtgctcgttttttccccaactactttgccatctggggcccaggcaccctcgtcaccgtctc gagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 930:

(SEQ ID NO: 940) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:941:

(SEQ ID NO: 951) caagtgctgacccagactgcatcgtccgtgtctgcagctgtgggaggcacagtcaccatcagttgccagtccagtcagagtgttactaataacaacgacttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctaccaggcatccaaactggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcgacctggagtgtgacgatgctgccacttactactgtcaaggcagttatagtggtggtatttgtgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 942:

(SEQ ID NO: 952) caagtgctgacccagactgcatcgtccgtgtctgcagctgtgggaggcacagtcaccatcagttgccagtccagtcagagtgttactaataacaacgacttagcctggtatcagcagaaaccagggcagcctcccaagctcctgatctaccaggcatccaaactggcatctggggtcccatcgcggttcaaaggcagtggatctgggacacagttcactctcaccatcagcgacctggagtgtgacgatgctgccacttactactgtcaaggcagttatagtggtggtatttgtgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 950:

(SEQ ID NO: 960) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 934; SEQ ID NO: 936; and SEQ ID NO: 938, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 921or the variable heavy chain sequence of SEQ ID NO: 922, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 954; SEQ ID NO: 956;and SEQ ID NO: 958, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 941 or the variable light chain sequence of SEQ ID NO: 942,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 933; SEQ ID NO: 935; SEQ ID NO: 937; and SEQ ID NO: 939,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 921 orthe variable heavy chain sequence of SEQ ID NO: 922, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 953; SEQ ID NO: 955; SEQID NO: 957; and SEQ ID NO: 959, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 941 or the variable light chain sequence of SEQ ID NO: 942, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 931 encoding the heavy chain sequence of SEQID NO: 921; the polynucleotide SEQ ID NO: 932 encoding the variableheavy chain sequence of SEQ ID NO: 922; the polynucleotide SEQ ID NO:951 encoding the light chain sequence of SEQ ID NO: 941; thepolynucleotide SEQ ID NO: 952 encoding the variable light chain sequenceof SEQ ID NO: 942; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 934; SEQ ID NO: 936; andSEQ ID NO: 938) of the heavy chain sequence of SEQ ID NO: 921 or thevariable heavy chain sequence of SEQ ID NO: 922; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 954; SEQ IDNO: 956; and SEQ ID NO: 958) of the light chain sequence of SEQ ID NO:941 or the variable light chain sequence of SEQ ID NO: 942;polynucleotides encoding the framework regions (SEQ ID NO: 933; SEQ IDNO: 935; SEQ ID NO: 937; and SEQ ID NO: 939) of the heavy chain sequenceof SEQ ID NO: 921 or the variable heavy chain sequence of SEQ ID NO:922; and polynucleotides encoding the framework regions (SEQ ID NO: 953;SEQ ID NO: 955; SEQ ID NO: 957; and SEQ ID NO: 959) of the light chainsequence of SEQ ID NO: 941 or the variable light chain sequence of SEQID NO: 942.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab25, the polynucleotidesencoding the full length Ab25 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 931 encoding the heavy chainsequence of SEQ ID NO: 921 and the polynucleotide SEQ ID NO: 951encoding the light chain sequence of SEQ ID NO: 941.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab25 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab25 or Fab fragments thereofmay be produced via expression of Ab25 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab26

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 961:

(SEQ ID NO: 971) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtacctatacaatgaactgggtccgccaggctccagggaaggggctggaatacatcggattcattagtagtagtagtagcatagattatgtgagttgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagagatttttatgctgattatattggtggtggttatccttacatctggggcccgggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 962:

(SEQ ID NO: 972) cagtcggtggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagtctctggattctccctcagtacctatacaatgaactgggtccgccaggctccagggaaggggctggaatacatcggattcattagtagtagtagtagcatagattatgtgagttgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatcaccagtccgacaaccgaggacacggccacctatttctgtgccagagatttttatgctgattatattggtggtggttatccttacatctggggcccgggcaccctcgtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 970:

(SEQ ID NO: 980) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:981:

(SEQ ID NO: 991) gccgatgttgtgatgacccagactccagcctccgtgtctgaacctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagtagctacttatcctggtatcagcagaaaccagggcagcctcccaagctcctgatctatggtgcatccaaactgacatctggggtcccatcgcggttcaaaggcagtggatctgggacagagtacactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcaaagcaattatgatatttatagttatgctttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 982:

(SEQ ID NO: 992) gccgatgttgtgatgacccagactccagcctccgtgtctgaacctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcattagtagctacttatcctggtatcagcagaaaccagggcagcctcccaagctcctgatctatggtgcatccaaactgacatctggggtcccatcgcggttcaaaggcagtggatctgggacagagtacactctcaccatcagcgacctggagtgtgccgatgctgccacttactactgtcaaagcaattatgatatttatagttatgctttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 990:

(SEQ ID NO: 1000) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 974; SEQ ID NO: 976; and SEQ ID NO: 978, which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 961or the variable heavy chain sequence of SEQ ID NO: 962, and/or one ormore of the polynucleotide sequences of SEQ ID NO: 994; SEQ ID NO: 996;and SEQ ID NO: 998, which correspond to the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain sequence ofSEQ ID NO: 981 or the variable light chain sequence of SEQ ID NO: 982,or combinations of these polynucleotide sequences. In another embodimentof the invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of polynucleotides encoding one or more of the CDRs, thevariable heavy chain and variable light chain sequences, and the heavychain and light chain sequences set forth above, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 973; SEQ ID NO: 975; SEQ ID NO: 977; and SEQ ID NO: 979,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 961 orthe variable heavy chain sequence of SEQ ID NO: 962, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 993; SEQ ID NO: 995; SEQID NO: 997; and SEQ ID NO: 999, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 981 or the variable light chain sequence of SEQ ID NO: 982, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 971 encoding the heavy chain sequence of SEQID NO: 961; the polynucleotide SEQ ID NO: 972 encoding the variableheavy chain sequence of SEQ ID NO: 962; the polynucleotide SEQ ID NO:991 encoding the light chain sequence of SEQ ID NO: 981; thepolynucleotide SEQ ID NO: 992 encoding the variable light chain sequenceof SEQ ID NO: 982; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 974; SEQ ID NO: 976; andSEQ ID NO: 978) of the heavy chain sequence of SEQ ID NO: 961 or thevariable heavy chain sequence of SEQ ID NO: 962; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 994; SEQ IDNO: 996; and SEQ ID NO: 998) of the light chain sequence of SEQ ID NO:981 or the variable light chain sequence of SEQ ID NO: 982;polynucleotides encoding the framework regions (SEQ ID NO: 973; SEQ IDNO: 975; SEQ ID NO: 977; and SEQ ID NO: 979) of the heavy chain sequenceof SEQ ID NO: 961 or the variable heavy chain sequence of SEQ ID NO:962; and polynucleotides encoding the framework regions (SEQ ID NO: 993;SEQ ID NO: 995; SEQ ID NO: 997; and SEQ ID NO: 999) of the light chainsequence of SEQ ID NO: 981 or the variable light chain sequence of SEQID NO: 982.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab26, the polynucleotidesencoding the full length Ab26 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 971 encoding the heavy chainsequence of SEQ ID NO: 961 and the polynucleotide SEQ ID NO: 991encoding the light chain sequence of SEQ ID NO: 981.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab26 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab26 or Fab fragments thereofmay be produced via expression of Ab26 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab27

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 1001:

(SEQ ID NO: 1011) cagtcgttggaggagtccgggggagacctggtcaagcctggaggaaccctgacactcacctgcacagcctctggattctccttcagtgacgaccactacatgtgctgggtccgccaggctccagggaaggggctgcagtggatcgcatgcatgtatgttggtagtagtggtgccacttattacgcgagctgggcgaaaggccgattcaccatctccaaaacctcgtcgaccacggtgactctgcaaatgaccagtctgacagccgcggacacggccacctatttctgtgcgagagatgattggactagttattatgcgtgggggtattgggccttgtggggcccgggcaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtct ccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 1002:

(SEQ ID NO: 1012) cagtcgttggaggagtccgggggagacctggtcaagcctggaggaaccctgacactcacctgcacagcctctggattctccttcagtgacgaccactacatgtgctgggtccgccaggctccagggaaggggctgcagtggatcgcatgcatgtatgttggtagtagtggtgccacttattacgcgagctgggcgaaaggccgattcaccatctccaaaacctcgtcgaccacggtgactctgcaaatgaccagtctgacagccgcggacacggccacctatttctgtgcgagagatgattggactagttattatgcgtgggggtattgggccttgtggggcccgggcac cctcgtcaccgtctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 1010:

(SEQ ID NO: 1020) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:1021:

(SEQ ID NO: 1031) gctgacattgtgatgacccagaatccagcctccgtgtctgaacctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcgttaatagttggttatcctggtatcagcagaaaccagggcagcctcccaagttcctgatctacaaggcatccactctggcatctggggtctcatcgcggttcaaaggcagtgggattgggacagagttcactctcaccatcagcgacctggagtgtgccgatgctgccacgtactattgccaatttagtaatagtggtactatttatgggagtggtttcggcggagggaccgaggtggtggtcaaacgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggaga gtgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 1022:

(SEQ ID NO: 1032) gctgacattgtgatgacccagaatccagcctccgtgtctgaacctgtgggaggcacagtcaccatcaagtgccaggccagtcagagcgttaatagttggttatcctggtatcagcagaaaccagggcagcctcccaagttcctgatctacaaggcatccactctggcatctggggtctcatcgcggttcaaaggcagtgggattgggacagagttcactctcaccatcagcgacctggagtgtgccgatgctgccacgtactattgccaatttagtaatagtggtactatttatgggagtggtttcggcggagggaccgaggtggtggtcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 1030:

(SEQ ID NO: 1040) acggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 1014; SEQ ID NO: 1016; and SEQ ID NO: 1018, which correspondto polynucleotides encoding the complementarity-determining regions(CDRs, or hypervariable regions) of the heavy chain sequence of SEQ IDNO: 1001 or the variable heavy chain sequence of SEQ ID NO: 1002, and/orone or more of the polynucleotide sequences of SEQ ID NO: 1034; SEQ IDNO: 1036; and SEQ ID NO: 1038, which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 1021 or the variable light chainsequence of SEQ ID NO: 1022, or combinations of these polynucleotidesequences. In another embodiment of the invention, the polynucleotidesencoding the antibodies of the invention or fragments thereof comprise,or alternatively consist of, combinations of polynucleotides encodingone or more of the CDRs, the variable heavy chain and variable lightchain sequences, and the heavy chain and light chain sequences set forthabove, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 1013; SEQ ID NO: 1015; SEQ ID NO: 1017; and SEQ ID NO: 1019,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 1001 orthe variable heavy chain sequence of SEQ ID NO: 1002, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 1033; SEQ ID NO: 1035; SEQID NO: 1037; and SEQ ID NO: 1039, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 1021 or the variable light chain sequence of SEQ ID NO: 1022, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 1011 encoding the heavy chain sequence of SEQID NO: 1001; the polynucleotide SEQ ID NO: 1012 encoding the variableheavy chain sequence of SEQ ID NO: 1002; the polynucleotide SEQ ID NO:1031 encoding the light chain sequence of SEQ ID NO: 1021; thepolynucleotide SEQ ID NO: 1032 encoding the variable light chainsequence of SEQ ID NO: 1022; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 1014; SEQ ID NO: 1016;and SEQ ID NO: 1018) of the heavy chain sequence of SEQ ID NO: 1001 orthe variable heavy chain sequence of SEQ ID NO: 1002; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 1034; SEQID NO: 1036; and SEQ ID NO: 1038) of the light chain sequence of SEQ IDNO: 1021 or the variable light chain sequence of SEQ ID NO: 1022;polynucleotides encoding the framework regions (SEQ ID NO: 1013; SEQ IDNO: 1015; SEQ ID NO: 1017; and SEQ ID NO: 1019) of the heavy chainsequence of SEQ ID NO: 1001 or the variable heavy chain sequence of SEQID NO: 1002; and polynucleotides encoding the framework regions (SEQ IDNO: 1033; SEQ ID NO: 1035; SEQ ID NO: 1037; and SEQ ID NO: 1039) of thelight chain sequence of SEQ ID NO: 1021 or the variable light chainsequence of SEQ ID NO: 1022.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab27, the polynucleotidesencoding the full length Ab27 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 1011 encoding the heavy chainsequence of SEQ ID NO: 1001 and the polynucleotide SEQ ID NO: 1031encoding the light chain sequence of SEQ ID NO: 1021.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab27 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab27 or Fab fragments thereofmay be produced via expression of Ab27 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

Antibody Ab28

In one embodiment, the invention is further directed to polynucleotidesencoding antibody polypeptides having binding specificity to HGF. In oneembodiment of the invention, polynucleotides of the invention comprise,or alternatively consist of, the following polynucleotide sequenceencoding the heavy chain sequence of SEQ ID NO: 1041:

(SEQ ID NO: 1051) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatgcaataagctgggtccgtcaggctccagggaaggggctggagtgggtcggagtcatttatgttattggtgtcactgactacgcgagctctgcgcaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctggctggaatcactttaacttgtggggccaagggaccctcgtcaccgtctcgagcgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacgcgagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, the polynucleotides of theinvention comprise, or alternatively consist of, the followingpolynucleotide sequence encoding the variable heavy chain polypeptidesequence of SEQ ID NO: 1042:

(SEQ ID NO: 1052) gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaatgcaataagctgggtccgtcaggctccagggaaggggctggagtgggtcggagtcatttatgttattggtgtcactgactacgcgagctctgcgcaaggccgattcaccatctccagagacaattccaagaacaccctgtatcttcaaatgaacagcctgagagctgaggacactgctgtgtattactgtgctagagtttatgattctggctggaatcactttaacttgtggggccaagggaccctcgtcaccgt ctcgagc.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant heavy chain polypeptide sequence of SEQID NO: 1050:

(SEQ ID NO: 1060) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacgcgagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgccagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the light chain polypeptide sequence of SEQ ID NO:1061:

(SEQ ID NO: 1071) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatgaagcatccaaactggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttgccaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg t.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO: 1062:

(SEQ ID NO: 1072) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccaggccagtcagagcattagcagttggttagcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatgaagcatccaaactggcatctggagtcccatcaaggttcagcggcagtggatctggaacagaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacaggcttatagtgttgccaatgttgataatgctttcggcggaggaaccaaggtggaaatcaaacgt.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the constant light chain polypeptide sequence of SEQID NO: 1070:

(SEQ ID NO: 1080) acggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc ttcaacaggggagagtgt.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 1054; SEQ ID NO: 1056; and SEQ ID NO: 1058, which correspondto polynucleotides encoding the complementarity-determining regions(CDRs, or hypervariable regions) of the heavy chain sequence of SEQ IDNO: 1041 or the variable heavy chain sequence of SEQ ID NO: 1042, and/orone or more of the polynucleotide sequences of SEQ ID NO: 1074; SEQ IDNO: 1076; and SEQ ID NO: 1078, which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe light chain sequence of SEQ ID NO: 1061 or the variable light chainsequence of SEQ ID NO: 1062, or combinations of these polynucleotidesequences. In another embodiment of the invention, the polynucleotidesencoding the antibodies of the invention or fragments thereof comprise,or alternatively consist of, combinations of polynucleotides encodingone or more of the CDRs, the variable heavy chain and variable lightchain sequences, and the heavy chain and light chain sequences set forthabove, including all of them.

In a further embodiment of the invention, polynucleotides encodingantibody fragments having binding specificity to HGF comprise, oralternatively consist of, one or more of the polynucleotide sequences ofSEQ ID NO: 1053; SEQ ID NO: 1055; SEQ ID NO: 1057; and SEQ ID NO: 1059,which correspond to polynucleotides encoding the framework regions (FRsor constant regions) of the heavy chain sequence of SEQ ID NO: 1041 orthe variable heavy chain sequence of SEQ ID NO: 1042, and/or one or moreof the polynucleotide sequences of SEQ ID NO: 1073; SEQ ID NO: 1075; SEQID NO: 1077; and SEQ ID NO: 1079, which correspond to the frameworkregions (FRs or constant regions) of the light chain sequence of SEQ IDNO: 1061 or the variable light chain sequence of SEQ ID NO: 1062, orcombinations of these polynucleotide sequences. In another embodiment ofthe invention, the polynucleotides encoding the antibodies of theinvention or fragments thereof comprise, or alternatively consist of,combinations of one or more of the FRs, the variable heavy chain andvariable light chain sequences, and the heavy chain and light chainsequences set forth above, including all of them.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding antibody fragments having binding specificity to HGF comprise,or alternatively consist of, one, two, three or more, including all ofthe following polynucleotides encoding antibody fragments: thepolynucleotide SEQ ID NO: 1051 encoding the heavy chain sequence of SEQID NO: 1041; the polynucleotide SEQ ID NO: 1052 encoding the variableheavy chain sequence of SEQ ID NO: 1042; the polynucleotide SEQ ID NO:1071 encoding the light chain sequence of SEQ ID NO: 1061; thepolynucleotide SEQ ID NO: 1072 encoding the variable light chainsequence of SEQ ID NO: 1062; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO: 1054; SEQ ID NO: 1056;and SEQ ID NO: 1058) of the heavy chain sequence of SEQ ID NO: 1041 orthe variable heavy chain sequence of SEQ ID NO: 1042; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO: 1074; SEQID NO: 1076; and SEQ ID NO: 1078) of the light chain sequence of SEQ IDNO: 1061 or the variable light chain sequence of SEQ ID NO: 1062;polynucleotides encoding the framework regions (SEQ ID NO: 1053; SEQ IDNO: 1055; SEQ ID NO: 1057; and SEQ ID NO: 1059) of the heavy chainsequence of SEQ ID NO: 1041 or the variable heavy chain sequence of SEQID NO: 1042; and polynucleotides encoding the framework regions (SEQ IDNO: 1073; SEQ ID NO: 1075;

SEQ ID NO: 1077; and SEQ ID NO: 1079) of the light chain sequence of SEQID NO: 1061 or the variable light chain sequence of SEQ ID NO: 1062.

In a preferred embodiment of the invention, polynucleotides of theinvention comprise, or alternatively consist of, polynucleotidesencoding Fab (fragment antigen binding) fragments having bindingspecificity for HGF. With respect to antibody Ab28, the polynucleotidesencoding the full length Ab28 antibody comprise, or alternativelyconsist of, the polynucleotide SEQ ID NO: 1051 encoding the heavy chainsequence of SEQ ID NO: 1041 and the polynucleotide SEQ ID NO: 1071encoding the light chain sequence of SEQ ID NO: 1061.

Another embodiment of the invention contemplates these polynucleotidesincorporated into an expression vector for expression in mammalian cellssuch as CHO, NSO, HEK-293, or in fungal, insect, or microbial systemssuch as yeast cells such as the yeast Pichia. Suitable Pichia speciesinclude, but are not limited to, Pichia pastoris. In one embodiment ofthe invention described herein (infra), Fab fragments may be produced byenzymatic digestion (e.g., papain) of Ab28 following expression of thefull-length polynucleotides in a suitable host. In another embodiment ofthe invention, anti-HGF antibodies such as Ab28 or Fab fragments thereofmay be produced via expression of Ab28 polynucleotides in mammaliancells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbialsystems such as yeast cells (for example diploid yeast such as diploidPichia) and other yeast strains. Suitable Pichia species include, butare not limited to, Pichia pastoris.

In one embodiment, the invention is directed to an isolatedpolynucleotide comprising a polynucleotide encoding an anti-HGF VHantibody amino acid sequence selected from SEQ ID NO: 12, SEQ ID NO: 52,SEQ ID NO: 92, SEQ ID NO: 132, SEQ ID NO: 172, SEQ ID NO: 212, SEQ IDNO: 252, SEQ ID NO: 292, SEQ ID NO: 332, SEQ ID NO: 372, SEQ ID NO: 412,SEQ ID NO: 452, SEQ ID NO: 492, SEQ ID NO: 532, SEQ ID NO: 572, SEQ IDNO: 612, SEQ ID NO: 652, SEQ ID NO: 692, SEQ ID NO: 732, SEQ ID NO: 772,SEQ ID NO: 812, SEQ ID NO: 852, SEQ ID NO: 892, SEQ ID NO: 932, SEQ IDNO: 972 SEQ ID NO: 1012, SEQ ID NO: 1052 or encoding a variant thereofwherein at least one framework residue (FR residue) has been substitutedwith an amino acid present at the corresponding position in a rabbitanti-HGF antibody VH polypeptide or a conservative amino acidsubstitution.

In another embodiment, the invention is directed to an isolatedpolynucleotide comprising the polynucleotide sequence encoding ananti-HGF VL antibody amino acid selected from SEQ ID NO: 32, SEQ ID NO:72, SEQ ID NO: 112, SEQ ID NO: 152, SEQ ID NO: 192, SEQ ID NO: 232, SEQID NO: 272, SEQ ID NO: 312, SEQ ID NO: 352, SEQ ID NO: 392, SEQ ID NO:432, SEQ ID NO: 472, SEQ ID NO: 512, SEQ ID NO: 552, SEQ ID NO: 592, SEQID NO: 632, SEQ ID NO: 672, SEQ ID NO: 712, SEQ ID NO: 752, SEQ ID NO:792, SEQ ID NO: 832, SEQ ID NO: 872, SEQ ID NO: 912, SEQ ID NO: 952, SEQID NO: 992, SEQ ID NO: 1032, or SEQ ID NO: 1072, or encoding a variantthereof wherein at least one framework residue (FR residue) has beensubstituted with an amino acid present at the corresponding position ina rabbit anti-HGF antibody VL polypeptide or a conservative amino acidsubstitution.

In yet another embodiment, the invention is directed to one or moreheterologous polynucleotides comprising a sequence encoding thepolypeptides contained in SEQ ID NO: 2 and SEQ ID NO: 22; SEQ ID NO: 42and SEQ ID NO: 62; SEQ ID NO: 82 and SEQ ID NO: 102; SEQ ID NO: 122 andSEQ ID NO: 142; SEQ ID NO: 162 and SEQ ID NO: 182; SEQ ID NO: 202 andSEQ ID NO: 222, SEQ ID NO: 242 and SEQ ID NO: 262; SEQ ID NO: 282 andSEQ ID NO: 302; SEQ ID NO: 322 and SEQ ID NO: 342; SEQ ID NO: 362 andSEQ ID NO: 382; SEQ ID NO: 402 and SEQ ID NO: 422; SEQ ID NO: 442 andSEQ ID NO: 462; SEQ ID NO: 482 and SEQ ID NO: 502; SEQ ID NO: 522 andSEQ ID NO: 542; SEQ ID NO: 562 and SEQ ID NO: 582; SEQ ID NO: 602 andSEQ ID NO: 622; SEQ ID NO: 642 and SEQ ID NO: 662; SEQ ID NO: 682 andSEQ ID NO: 702; SEQ ID NO: 722 and SEQ ID NO: 742; SEQ ID NO: 762 andSEQ ID NO: 782; SEQ ID NO: 802 and SEQ ID NO: 822; SEQ ID NO: 842 andSEQ ID NO: 862; SEQ ID NO: 882 and SEQ ID NO: 902; SEQ ID NO: 922 andSEQ ID NO: 942, SEQ ID NO: 962, SEQ ID NO: 982, SEQ ID NO: 1002, SEQ IDNO: 1022, and SEQ ID NO: 1042 and SEQ ID NO: 1062

In another embodiment, the invention is directed to an isolatedpolynucleotide that expresses a polypeptide containing at least one CDRpolypeptide derived from an anti-HGF antibody according to the inventionsuch as Ab1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23,Ab24, Ab25, and Ab28, wherein said expressed polypeptide alonespecifically binds HGF or specifically binds HGF when expressed inassociation with another polynucleotide sequence that expresses apolypeptide containing at least one CDR polypeptide derived from ananti-HGF antibody wherein said at least one CDR is selected from thosecontained in the VL or VH polypeptides of SEQ ID NOS: 2, 22, 42, 62, 82,102, 122, 142, 162, 182, 202, 222, 242, 262, 282, 302, 322, 342, 362,382, 402, 422, 442, 462, 482, 502, 522, 542, 562, 582, 602, 622, 642,662, 682, 702, 722, 742, 762, 782, 802, 822, 842, 862, 882, 902, 922,942, 962, 982, 1002, 1022, 1042, and 1062. More specifically, the atleast one CDR comprises SEQ ID NOS: 4, 6, 8, 24, 26, 28, 44, 46, 48, 64,66, 68, 84, 86, 88, 104, 106, 108, 124, 126, 128, 144, 146, 148, 164,166, 168, 184, 186, 188, 204, 206, 208, 224, 226, 228, 244, 246, 248,264, 266, 268, 284, 286, 288, 304, 306, 308, 324, 326, 328, 344, 346,348, 364, 366, 368, 384, 386, 388, 404, 406, 408, 424, 426, 428, 444,446, 448, 464, 466, 468, 484, 486, 488, 504, 506, 508, 524, 526, 528,544, 546, 548, 564, 566, 568, 584, 586, 588, 604, 606, 608, 624, 626,628, 644, 646, 648, 664, 666, 668, 684, 686, 688, 704, 706, 708, 724,726, 728, 744, 746, 748, 764, 766, 768, 784, 786, 788, 804, 806, 808,824, 826, 828, 844, 846, 848, 864, 866, 884, 886, 888, 904, 906, 908,924, 926, 928, 944, 946, or 948, 964, 966, 968, 984, 986, or 988; 1004,1006, 1008, 1024, 1026, or 1028; 1044, 1046, 1048, 1064, 1066, or 1068.

Host cells and vectors comprising said polynucleotides are alsocontemplated.

The invention further contemplates vectors comprising the polynucleotidesequences encoding the variable heavy and light chain polypeptidesequences, as well as the individual complementarity-determining regions(CDRs, or hypervariable regions), as set forth herein, as well as hostcells comprising said vector sequences. In one embodiment of theinvention, the host cell is a yeast cell. In another embodiment of theinvention, the yeast host cell belongs to the genus Pichia.

Anti-HGF Activity

The anti-HGF antibodies of the present invention, and fragments thereofhaving binding specificity to HGF, may also be described by theirstrength of binding or their affinity for HGF. In one embodiment of theinvention, the anti-HGF antibodies of the present invention, andfragments thereof having binding specificity to HGF, bind to HGF with adissociation constant (K_(D)) of less than or equal to 5×10⁻⁷, 10⁻⁷,5×10⁻⁸, 10⁻⁸, 5×10⁻⁹, 10⁻⁹, 5×10¹⁰, 10⁻¹⁰, 5×10⁻¹¹, 10⁻¹¹, 5×10⁻¹²,10⁻¹², 5×10⁻¹³, 10⁻¹³, 5×10⁻¹⁴, 10⁻¹⁴, 5×10⁻¹⁵ or 10⁻¹⁵.

Preferably, the anti-HGF antibodies and fragments thereof bind HGF witha dissociation constant of less than or equal to 5×10⁻¹⁰. In anotherembodiment of the invention, the anti-HGF antibodies of the presentinvention, and fragments thereof having binding specificity to HGF, bindto a linear or conformational HGF epitope.

In another embodiment of the invention, the anti-HGF antibodies of thepresent invention, and fragments thereof having binding specificity toHGF, bind to HGF with an off-rate of less than or equal to 10⁻⁴ S⁻¹,5×10⁻⁵ S⁻¹, 10⁻⁵ S⁻¹, 5×10⁻⁶ S⁻¹, 10⁻⁶ S⁻¹, 5×10⁻⁷ S⁻¹, or 10⁻⁷ S⁻¹.

In another embodiment of the invention, the anti-HGF antibodies of thepresent invention, and fragments thereof having binding specificity toHGF, including those having binding affinities or dissociation constantsdescribed above, inhibit or block at least one HGF-associated biologicalactivity. The term “HGF biological activity” when used herein refers toany mitogenic, motogenic or morphogenic activity of HGF or anyactivities occurring as a result of HGF binding to a HGF receptor. Inparticular, the subject antibodies and antibody fragments may be used toinhibit or block HGF-associated cell proliferation, invasion,scattering, metastasis, angiogenesis, fibrosis, and c-met or HGFreceptor activation.

The term “HGF receptor or c-met activation” refers to HGF receptordimerization or HGF receptor-induced tyrosine kinase activity. HGFreceptor activation may occur as a result of HGF binding to a HGFreceptor, but may alternatively occur independent of any HGF binding toa HGF receptor. HGF biological activity may, for example, be determinedin an in vitro or in vivo assay of hepatocyte growth promotion, e.g., asdescribed in the working examples. Adult rat hepatocytes in primaryculture may be used to test the effect of HGF on hepatocyteproliferation or more preferably the disclosed method for evaluating theeffect of anti-HGF antibodies or fragments on the proliferation of4mBr-5 cells disclosed in Example 12 infra.

In a further embodiment of the invention, the anti-HGF activity of theanti-HGF antibodies of the present invention, and fragments thereofhaving binding specificity to HGF, exhibit anti-HGF activity bypreventing, ameliorating or reducing the symptoms of, or alternativelytreating, diseases and disorders associated with HGF. Non-limitingexamples of diseases and disorders associated with HGF are set forthinfra.

B-Cell Screening and Isolation

In one embodiment, the present invention contemplates the preparationand isolation of a clonal population of antigen-specific B cells thatmay be used for isolating at least one HGF antigen-specific cell, whichcan be used to produce a monoclonal antibody against HGF, which isspecific to a desired HGF antigen, or a nucleic acid sequencecorresponding to such an antibody. Methods of preparing and isolatingsaid clonal population of antigen-specific B cells are taught, forexample, in U.S. patent publication no. US 2007/0269868 toCarvalho-Jensen et al., the disclosure of which is herein incorporatedby reference in its entirety. Methods of preparing and isolating saidclonal population of antigen-specific B cells are also taught herein inthe examples. Methods of “enriching” a cell population by size ordensity are known in the art. See, e.g., U.S. Pat. No. 5,627,052. Thesesteps can be used in addition to enriching the cell population byantigen-specificity.

Methods of Humanizing Antibodies

In another embodiment, the present invention contemplates methods forhumanizing antibody heavy and light chains. Methods for humanizingantibody heavy and light chains which may be applied to anti-HGFantibodies are taught, for example, in U.S. patent applicationpublication no. US 2009/0022659 to Olson et al., and in U.S. Pat. No.7,935,340 to Garcia-Martinez et al., the disclosures of each of whichare herein incorporated by reference in their entireties.

Methods of Producing Antibodies and Fragments Thereof

In another embodiment, the present invention contemplates methods forproducing anti-HGF antibodies and fragments thereof. Methods forproducing anti-HGF antibodies and fragments thereof secreted frompolyploidal, preferably diploid or tetraploid strains of matingcompetent yeast are taught, for example, in U.S. patent applicationpublication no. US 2009/0022659 to Olson et al., and in U.S. Pat. No.7,935,340 to Garcia-Martinez et al., the disclosures of each of whichare herein incorporated by reference in their entireties. A preferredyeast for manufacture of antibodies is Pichia, and more preferablyPichia pastoris. However, antibodies according to the inventionpotentially may also be made in other yeast such as other matingcompetent yeast of the Saccharomycetaceae family, which includes thegenera Arxiozyma; Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera;Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea;Lodderomyces; Pachysolen; Pichia; Saccharomyces; Saturnispora;Tetrapisispora; Torulaspora; Williopsis; and Zygosaccharomyces. Othertypes of yeast potentially useful for making antibody proteins accordingto the invention include Yarrowia; Rhodosporidium; Candida; Hansenula;Filobasium; Sporidiobolus; Bullera; Leucosporidium and Filobasidella.Such yeast strain may be haploid or polyploid.

Other methods of producing antibodies are well known to those ofordinary skill in the art. For example, methods of producing chimericantibodies are now well known in the art (See, for example, U.S. Pat.No. 4,816,567 to Cabilly et al.; Morrison et al., P.N.A.S. USA,81:8651-55 (1984); Neuberger, M. S. et al., Nature, 314:268-270 (1985);Boulianne, G. L. et al., Nature, 312:643-46 (1984), the disclosures ofeach of which are herein incorporated by reference in their entireties).

Likewise, other methods of producing humanized antibodies are now wellknown in the art (See, for example, U.S. Pat. Nos. 5,530,101, 5,585,089,5,693,762, and 6,180,370 to Queen et al; U.S. Pat. Nos. 5,225,539 and6,548,640 to Winter; U.S. Pat. Nos. 6,054,297, 6,407,213 and 6,639,055to Carter et al; U.S. Pat. No. 6,632,927 to Adair; Jones, P. T. et al,Nature, 321:522-525 (1986); Reichmann, L., et al, Nature, 332:323-327(1988); Verhoeyen, M, et al, Science, 239:1534-36 (1988), thedisclosures of each of which are herein incorporated by reference intheir entireties).

Antibody polypeptides of the invention having HGF binding specificitymay also be produced by constructing, using conventional techniques wellknown to those of ordinary skill in the art, an expression vectorcontaining an operon and a DNA sequence encoding an antibody heavy chainin which the DNA sequence encoding the CDRs required for antibodyspecificity is derived from a non-human cell source, preferably a rabbitB-cell source, while the DNA sequence encoding the remaining parts ofthe antibody chain is derived from a human cell source.

A second expression vector is produced using the same conventional meanswell known to those of ordinary skill in the art, said expression vectorcontaining an operon and a DNA sequence encoding an antibody light chainin which the DNA sequence encoding the CDRs required for antibodyspecificity is derived from a non-human cell source, preferably a rabbitB-cell source, while the DNA sequence encoding the remaining parts ofthe antibody chain is derived from a human cell source.

The expression vectors are transfected into a host cell by conventiontechniques well known to those of ordinary skill in the art to produce atransfected host cell, said transfected host cell cultured byconventional techniques well known to those of ordinary skill in the artto produce said antibody polypeptides.

The host cell may be co-transfected with the two expression vectorsdescribed above, the first expression vector containing DNA encoding anoperon and a light chain-derived polypeptide and the second vectorcontaining DNA encoding an operon and a heavy chain-derived polypeptide.The two vectors contain different selectable markers, but preferablyachieve substantially equal expression of the heavy and light chainpolypeptides. Alternatively, a single vector may be used, the vectorincluding DNA encoding both the heavy and light chain polypeptides. Thecoding sequences for the heavy and light chains may comprise cDNA,genomic DNA, or both.

Host cells which potentially may be used to express the subject antibodypolypeptides may include bacterial cells such as E. coli, or eukaryoticcells such as P. pastoris, other yeast cells, fungi, insect cells,mammalian cells, and plant cells. In one embodiment of the invention, amammalian cell of a well-defined type may be for this purpose, such as amyeloma cell, a Chinese hamster ovary (CHO) cell line, a NSO cell line,or a HEK293 cell line.

The general methods by which the vectors may be constructed,transfection methods required to produce the host cell and culturingmethods required to produce the antibody polypeptides from said hostcells all include conventional techniques. Although preferably the cellline used to produce the antibody is a mammalian cell line, any othersuitable cell line, such as a bacterial cell line such as an E.coli-derived bacterial strain, or a yeast cell line, may alternativelybe used.

Similarly, once produced the antibody polypeptides may be purifiedaccording to standard procedures in the art, such as for examplecross-flow filtration, ammonium sulphate precipitation, affinity columnchromatography and the like.

The antibody polypeptides described herein may also be used for thedesign and synthesis of either peptide or non-peptide mimetics thatwould be useful for the same therapeutic applications as the antibodypolypeptides of the invention. See, for example, Saragobi et al,Science, 253:792-795 (1991), the contents of which is hereinincorporated by reference in its entirety.

Screening Assays

The invention also includes screening assays designed to assist in theidentification of diseases and disorders associated with HGF in patientsexhibiting symptoms of a HGF associated disease or disorder.

In some embodiments, the antibody is used as a diagnostic tool. Theantibody can be used to assay the amount of HGF present in a sampleand/or subject. As will be appreciated by one of skill in the art, suchantibodies need not be neutralizing antibodies. In some embodiments, thediagnostic antibody is not a neutralizing antibody. In some embodiments,the diagnostic antibody binds to a different epitope than theneutralizing antibody binds to. In some embodiments, the two antibodiesdo not compete with one another.

In some embodiments, the antibodies disclosed herein are used orprovided in an assay kit and/or method for the detection of HGF inmammalian tissues or cells in order to screen/diagnose for a disease ordisorder associated with changes in levels of HGF. The kit comprises anantibody that binds HGF and means for indicating the binding of theantibody with HGF, if present, and optionally HGF protein levels.Various means for indicating the presence of an antibody can be used.For example, fluorophores, other molecular probes, or enzymes can belinked to the antibody and the presence of the antibody can be observedin a variety of ways. The method for screening for such disorders caninvolve the use of the kit, or simply the use of one of the disclosedantibodies and the determination of whether the antibody binds to HGF ina sample. As will be appreciated by one of skill in the art, high orelevated levels of HGF will result in larger amounts of the antibodybinding to HGF in the sample. Thus, degree of antibody binding can beused to determine how much HGF is in a sample. Subjects or samples withan amount of HGF that is greater than a predetermined amount (e.g., anamount or range that a person without a HGF related disorder would have)can be characterized as having a HGF mediated disorder. In someembodiments, the antibody is administered to a subject taking a statin,in order to determine if the statin has affected the amount of HGF inthe subject.

The invention is also directed to a method of in vivo imaging whichdetects the presence of cells which express HGF comprising administeringa diagnostically effective amount of a diagnostic composition. Said invivo imaging is useful for the detection or imaging of HGF expressingcells or organs, for example, and can be useful as part of a planningregimen for the design of an effective cancer treatment protocol. Thetreatment protocol may include, for example, one or more of radiation,chemotherapy, cytokine therapy, gene therapy, and antibody therapy, aswell as an anti-HGF antibody or fragment thereof

The present invention further provides for a kit for detecting bindingof an anti-HGF antibody of the invention to HGF. In particular, the kitmay be used to detect the presence of a HGF specifically reactive withan anti-HGF antibody of the invention or an immunoreactive fragmentthereof. The kit may also include an antibody bound to a substrate, asecondary antibody reactive with the antigen and a reagent for detectinga reaction of the secondary antibody with the antigen. Such a kit may bean ELISA kit and can comprise the substrate, primary and secondaryantibodies when appropriate, and any other necessary reagents such asdetectable moieties, enzyme substrates, and color reagents, for exampleas described herein. The diagnostic kit may also be in the form of animmunoblot kit. The diagnostic kit may also be in the form of achemiluminescent kit (Meso Scale Discovery, Gaithersburg, Md.). Thediagnostic kit may also be a lanthanide-based detection kit(PerkinElmer, San Jose, Calif.).

A skilled clinician would understand that a biological sample includes,but is not limited to, sera, plasma, urine, saliva, mucous, pleuralfluid, synovial fluid and spinal fluid.

Methods of Ameliorating or Reducing Symptoms of or Treating, orPreventing, Diseases and Disorders Associated with HGF and/or theHGF/HGF-R(c-Met) Interaction and/or c-Met Activation

The anti-HGF antibodies described herein, or fragments thereof, based ontheir binding and functional properties are well suited for amelioratingor reducing the symptoms of, or treating, or preventing, diseases anddisorders associated with HGF including those associated with theHGF/HGF-R interaction and HGF associated c-met activation. Anti-HGFantibodies described herein, or fragments thereof, as well ascombinations, can also be administered in a therapeutically effectiveamount to patients in need of treatment of diseases and disordersassociated with HGF in the form of a pharmaceutical composition asdescribed in greater detail below.

In one embodiment of the invention, anti-HGF antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, the following non-limitinglisting of diseases and disorders: cancers, including ovarian cancer,breast cancer, lung cancer (small cell or non-small cell), colon andcolorectal cancer, prostate cancer, pancreatic cancer, renal cancer,gastric cancer, liver cancer, bladder cancer, thyroid cancer,endometrial cancer, head-and-neck tumors, melanoma, sarcomas, leukemias;lymphomas; and brain tumors (e.g., glioblastomas), of children oradults; macular degeneration; Alzheimer's disease; and malarialinfection. In a preferred embodiment, the disease is selected from acancer or macular degeneration.

In another embodiment of the invention, the invention provides use of ananti-HGF antibody of the invention in the preparation of a medicamentfor the therapeutic and/or prophylactic treatment of a disease, such asa cancer, a tumor, a cell proliferative disorder, an immune (such asautoimmune) disorder and/or an angiogenesis-related disorder. In anotherembodiment of the invention, the invention provides use of a nucleicacid of the invention in the preparation of a medicament for thetherapeutic and/or prophylactic treatment of a disease, such as acancer, a tumor, a cell proliferative disorder, an immune (such asautoimmune) disorder and/or an angiogenesis-related disorder.

In another embodiment of the invention, the invention provides use of anexpression vector of the invention in the preparation of a medicamentfor the therapeutic and/or prophylactic treatment of a disease, such asa cancer, a tumor, a cell proliferative disorder, an immune (such asautoimmune) disorder and/or an angiogenesis-related disorder. In anotherembodiment of the invention, the invention provides use of a host cellof the invention in the preparation of a medicament for the therapeuticand/or prophylactic treatment of a disease, such as a cancer, a tumor, acell proliferative disorder, an immune (such as autoimmune) disorderand/or an angiogenesis-related disorder. In another embodiment of theinvention, the invention provides the use of an article of manufactureof the invention in the preparation of a medicament for the therapeuticand/or prophylactic treatment of a disease, such as a cancer, a tumor, acell proliferative disorder, an immune (such as autoimmune) disorderand/or an angiogenesis-related disorder.

In another aspect, the invention provides use of a kit of the inventionin the preparation of a medicament for the therapeutic and/orprophylactic treatment of a disease, such as a cancer, a tumor, a cellproliferative disorder, an immune (such as autoimmune) disorder and/oran angiogenesis-related disorder.

In a preferred embodiment of the invention, the invention providesmethods and compositions useful for modulating disease states associatedwith dysregulation of the HGF/c-met signaling axis. The HGF/c-metsignaling pathway is involved in multiple biological and physiologicalfunctions, including, e.g., cell proliferation and angiogenesis. Thus,in one aspect, the invention provides a method comprising administeringto a subject an antibody of the invention. In one aspect, the inventionprovides a method of inhibiting c-met activated cell proliferation, saidmethod comprising contacting a cell or tissue with an effective amountof an antibody of the invention, whereby cell proliferation associatedwith c-met activation is inhibited. In another aspect, the inventionprovides a method of treating a pathological condition associated withdysregulation of c-met activation in a subject, said method comprisingadministering to the subject an effective amount of an antibody of theinvention, whereby said condition is treated. In another aspect, theinvention provides a method of inhibiting the growth of a cell thatexpresses c-met or hepatocyte growth factor, or both, said methodcomprising contacting said cell with an antibody of the inventionthereby causing an inhibition of growth of said cell. In one embodiment,the cell is contacted by HGF expressed by a different cell (e.g.,through a paracrine effect). In another aspect, the invention provides amethod of therapeutically treating a mammal having a cancerous tumorcomprising a cell that expresses c-met or hepatocyte growth factor, orboth, said method comprising administering to said mammal an effectiveamount of an antibody of the invention, thereby effectively treatingsaid mammal. In one embodiment, the cell is contacted by HGF expressedby a different cell (e.g., through a paracrine effect). In anotheraspect, the invention provides a method for treating or preventing acell proliferative disorder associated with increased expression oractivity of c-met or hepatocyte growth, or both, said method comprisingadministering to a subject in need of such treatment an effective amountof an antibody of the invention, thereby effectively treating orpreventing said cell proliferative disorder. In one embodiment, saidproliferative disorder is cancer. In another aspect, the inventionprovides a method for inhibiting the growth of a cell, wherein growth ofsaid cell is at least in part dependent upon a growth potentiatingeffect of c-met or hepatocyte growth factor, or both, said methodcomprising contacting said cell with an effective amount of an antibodyof the invention, thereby inhibiting the growth of said cell. In oneembodiment, the cell is contacted by HGF expressed by a different cell(e.g., through a paracrine effect).

In another aspect, the invention provides a method of therapeuticallytreating a tumor in a mammal, wherein the growth of said tumor is atleast in part dependent upon a growth potentiating effect of c-met orhepatocyte growth factor, or both, said method comprising contactingsaid cell with an effective amount of an antibody of the invention,thereby effectively treating said tumor. In one embodiment, the cell iscontacted by HGF expressed by a different cell (e.g., through aparacrine effect).

Methods of the invention can be used to treat any suitable pathologicalstate wherein antagonizing HGF or the HGF/c-met interaction istherapeutically beneficial, for example, cells and/or tissues associatedwith dysregulation of the HGF/c-met signaling pathway. In oneembodiment, a cell that is targeted in a method of the invention is acancer cell. For example, a cancer cell can be one selected from thegroup consisting of a breast cancer cell, a colorectal cancer cell, alung cancer cell, a papillary carcinoma cell (e.g., of the thyroidgland), a colon cancer cell, a pancreatic cancer cell, an ovarian cancercell, a cervical cancer cell, a central nervous system cancer cell, anosteogenic sarcoma cell, a renal carcinoma cell, a hepatocellularcarcinoma cell, a bladder cancer cell, a gastric carcinoma cell, a headand neck squamous carcinoma cell, a melanoma cell and a leukemia cell.In one embodiment, a cell that is targeted in a method of the inventionis a hyperproliferative and/or hyperplastic cell. In one embodiment, acell that is targeted in a method of the invention is a dysplastic cell.In yet another embodiment, a cell that is targeted in a method of theinvention is a metastatic cell.

Methods of the invention can further comprise additional treatmentsteps. For example, in one embodiment, a method further comprises a stepwherein a targeted cell and/or tissue (e.g., a cancer cell) is exposedto radiation treatment or a chemotherapeutic agent.

As noted, c-met activation is an important biological process thedysregulation of which leads to numerous pathological conditions.Accordingly, in one embodiment of methods of the invention, a cell thatis targeted (e.g., a cancer cell) is one in which activation of c-met isenhanced as compared to a normal cell of the same tissue origin. In oneembodiment, a method of the invention causes the death of a targetedcell. For example, contact with an antagonist of the invention mayresult in a cell's inability to signal through the c-met pathway, whichresults in cell death.

Dysregulation of c-met activation (and thus signaling) can result from anumber of cellular changes, including, for example, overexpression ofHGF (c-met's cognate ligand) and/or c-met itself. Accordingly, in someembodiments, a method of the invention comprises targeting a cellwherein c-met or hepatocyte growth factor, or both, is more abundantlyexpressed by said cell (e.g., a cancer cell) as compared to a normalcell of the same tissue origin. A c-met-expressing cell can be regulatedby HGF from a variety of sources, i.e. in an autocrine or paracrinemanner. For example, in one embodiment of methods of the invention, atargeted cell is contacted/bound by hepatocyte growth factor expressedin a different cell (e.g., via a paracrine effect). Said different cellcan be of the same or of a different tissue origin. In one embodiment, atargeted cell is contacted/bound by HGF expressed by the targeted cellitself (e.g., via an autocrine effect/loop). c-met activation and/orsignaling can also occur independent of ligand. Hence, in one embodimentof methods of the invention, c-met activation in a targeted cell occursindependent of ligand.

A disorder treated with an anti-HGF antibody or fragment of theinvention includes any condition that would benefit from treatment witha an anti-HGF antibody or fragment or method of use thereof according tothe invention. This includes chronic and acute disorders or diseasesincluding those pathological conditions which predispose the mammal tothe disorder in question. Non-limiting examples of disorders to betreated herein include malignant and benign tumors; non-leukemias andlymphoid malignancies; neuronal, glial, astrocytal, hypothalamic andother glandular, macrophagal, epithelial, stromal and blastocoelicdisorders; and inflammatory, immunologic and other angiogenesis-relateddisorders. As noted previously, cell proliferative disorders treatableaccording to the invention include disorders that are associated withsome degree of abnormal cell proliferation. In one embodiment, the cellproliferative disorder is cancer.

Specific examples of such cancers include squamous cell cancer,small-cell lung cancer, non-small cell lung cancer, adenocarcinoma ofthe lung, squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, colorectal cancer,endometrial or uterine carcinoma, salivary gland carcinoma, kidneycancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma and various types of head and neck cancer.

Another type of disorder that may be treated with an anti-HGF antibodyor fragment of the invention includes those involving dysregulation ofangiogenesis. These disorders include both non-neoplastic and neoplasticconditions. Neoplastics include but are not limited those cancers dabove. Non-neoplastic disorders include but are not limited to undesiredor aberrant hypertrophy, arthritis, rheumatoid arthritis (RA),psoriasis, psoriatic plaques, sarcoidosis, atherosclerosis,atherosclerotic plaques, diabetic and other proliferative retinopathiesincluding retinopathy of prematurity, retrolental fibroplasia,neovascular glaucoma, age-related macular degeneration, diabetic macularedema, corneal neovascularization, corneal graft neovascularization,corneal graft rejection, retinal/choroidal neovascularization,neovascularization of the angle (rubeosis), ocular neovascular disease,vascular restenosis, arteriovenous malformations (AVM), meningioma,hemangioma, angiofibroma, thyroid hyperplasias (including Grave'sdisease), corneal and other tissue transplantation, chronicinflammation, lung inflammation, acute lung injury/ARDS, sepsis, primarypulmonary hypertension, malignant pulmonary effusions, cerebral edema(e.g., associated with acute stroke/closed head injury/trauma), synovialinflammation, pannus formation in RA, myositis ossificans, hypertropicbone formation, osteoarthritis (OA), refractory ascites, polycysticovarian disease, endometriosis, 3rd spacing of fluid diseases(pancreatitis, compartment syndrome, burns, bowel disease), uterinefibroids, premature labor, chronic inflammation such as IBD (Crohn'sdisease and ulcerative colitis), renal allograft rejection, inflammatorybowel disease, nephrotic syndrome, undesired or aberrant tissue massgrowth (non-cancer), hemophilic joints, hypertrophic scars, inhibitionof hair growth, Osler-Weber syndrome, pyogenic granuloma retrolentalfibroplasias, scleroderma, trachoma, vascular adhesions, synovitis,dermatitis, preeclampsia, ascites, pericardial effusion (such as thatassociated with pericarditis), and pleural effusion.

In preferred embodiments, an antibody to HGF is used with one or moreother therapeutic agents or regimens used to treat various cancers. Incertain embodiments, an antibody to HGF is used with one or moreparticular therapeutic agents to treat or prevent malaria. In certainembodiments, an antibody specific to HGF is used with one or moreparticular therapeutic agents to treat or prevent proliferative diabeticretinopathy. In certain embodiments, in view of the condition and thedesired level of treatment, two, three, or more agents may beadministered. In certain embodiments, such agents may be providedtogether by inclusion in the same formulation. In certain embodiments,such agents and a specific binding agent to HGF may be provided togetherby inclusion in the same formulation. In certain embodiments, suchagents may be formulated separately and provided together by inclusionin a treatment kit. In certain embodiments, such agents and a specificbinding agent to HGF may be formulated separately and provided togetherby inclusion in a treatment kit. In certain embodiments, such agents maybe provided separately.

Methods of the invention may be useful for ameliorating and/or treatingdiseases or conditions involving aberrant angiogenesis. “Aberrantangiogenesis,” as used herein refers to angiogenesis that does not occurin normal biological processes such as development, reproduction, woundhealing etc. Angiogenesis that may be reduced using methods of theinvention may be stimulated, in some embodiments, by a factor selectedfrom the group consisting of vascular endothelial growth factor (VEGF),basic fibroblast growth factor (bFGF), lipopolysaccharide (LPS),epidermal growth factor (EGF), interleukin-6 (IL-6), platelet-derivedgrowth factor (PDGF), tumor necrosis factor (TNFalpha), hepatocytegrowth factor (HGF), and combinations thereof

As angiogenesis is involved in a variety of pathologic processes, itleinventive methods may be useful in treating and/or ameliorating diseasessuch as, for example cancer (including metastatic cancer), ocularneovascularization (such as macular degeneration), inflammatory diseases(such as arthritis), etc.

Tumors often come to depend on the formation of new blood vessels inorder to continue growing and/or develop metastases. Thus, inventivemethods may be useful in ameliorating and/or treating tumors. Subjectsthat may be administered chlorotoxin agents may have tumors that arebeginning to metastasize or have already metastasized. Subjects may haveone or more metastases. In some embodiments, sizes of tumors and/ormetastases are reduced.

In some embodiments, the subject is suffering from or at risk for acondition or disease characterized by choroidal neovascularization. Suchconditions include, but are not limited to, macular degeneration,myopia, ocular trauma, pseudoxanthoma elasticum, and combinationsthereof

Macular degeneration is the leading cause of vision loss and blindnessin Americans aged 65 and older. Macular dengeration typically occurs inthe age-related form (often called AMD or ARMD), though juvenile maculardegeneration occurs as well. In AMD/ARMD, the macula—the part of theretina that is responsible for sharp, central vision—degenerates.Macular degeneration is typically diagnosed as either dry(non-neovascular) or wet (neovascular). In dry macular degeneration,yellowish spots known as drusen begin to accumulate from deposits ordebris from deteriorating tissue from mostly around the macula. Centralvision less usually occurs gradually and is not as severe as vision lossin wet macular degeneration.

Wet macular degeneration, as the “neovascular” designation suggests, ischaracterized by new blood vessels growing aberrantly, e.g., on themacula. Such new blood vessels may grow beneath the retina, leakingblood and fluid. Such leakage causes permanent damage to light-sensitiveretinal cells, which die and create blind spots in central vision. Wetmacular degeneration may be further grouped into two categories. In theoccult form of wet macular degeneration, new blood vessel growth beneaththe retina is not as pronounced and leakage is less evident, typicallyresulting in less severe vision less. In the classic form of wet maculardegeneration, blood vessel growth and scarring have very clear,delineated outlines that are observable beneath the retina. Classic wetmacular degeneration is also known as classic choroidalneovascularization and usually results in more severe vision loss.

Given the role of angiogenesis in wet macular degeneration, whichcomprises many AMD/ARMD cases, inventive methods may be useful intreating and/or ameliorating such disorders. Current therapies for wetmacular degeneration involve angiogenesis inhibitors such as Lucentis™,Macugen™, and/or Visudyne™, optionally combined with photodynamictherapy (PDT) to target drugs to specific cells. Photocoagulation, inwhich a high energy laser beam is used to create small burns in areas ofthe retina with abnormal blood vessels, is also used to treat wetmacular degeneration.

In some embodiments, the subject suffers from wet macular degenerationand/or age-related macular degeneration. Among subjects suffering fromwet macular degeneration, subjects may suffer from the occult or theclassic form. In some embodiments, chlorotoxin agents cause regressionof existing neovasculature. In some embodiments, chlorotoxin agentsprevent sprouting of new vessels. In certain embodiments, chlorotoxinagents are combined with other treatments for wet macular degeneration,such as photocoagulation, treatment with other angiogenesis inhibitors,photodynamic therapy, etc.

The foregoing is intended to be exemplary of diseases and conditionswherein administration of an anti-HGF antibody or fragment according tothe invention may be therapeutically beneficial.

Administration

In one embodiment of the invention, the anti-HGF antibodies describedherein, or HGF binding fragments thereof, as well as combinations ofsaid antibodies or antibody fragments, are administered to a subject ata concentration of between about 0.1 and 10.0 mg/kg of body weight ofrecipient subject. In a preferred embodiment of the invention, theanti-HGF antibodies described herein, or HGF binding fragments thereof,as well as combinations of said antibodies or antibody fragments, areadministered to a subject at a concentration of about 0.4 mg/kg of bodyweight of recipient subject. In a preferred embodiment of the invention,the anti-HGF antibodies described herein, or HGF binding fragmentsthereof, as well as combinations of said antibodies or antibodyfragments, are administered to a recipient subject with a frequency ofonce every twenty-six weeks or less, such as once every sixteen weeks orless, once every eight weeks or less, or once every four weeks or less.

A person of skill in the art would be able to determine an effectivedosage and frequency of administration through routine experimentation,for example guided by the disclosure herein and the teachings inGoodman, L. S., Gilman, A., Brunton, L. L., Lazo, J. S., & Parker, K. L.(2006). Goodman & Gilman's the pharmacological basis of therapeutics.New York: McGraw-Hill; Howland, R. D., Mycek, M. J., Harvey, R. A.,Champe, P. C., & Mycek, M. J. (2006). Pharmacology. Lippincott'sillustrated reviews. Philadelphia: Lippincott Williams & Wilkins; andGolan, D. E. (2008). Principles of pharmacology: the pathophysiologicbasis of drug therapy. Philadelphia, Pa., [etc.]: Lippincott Williams &Wilkins.

In another embodiment of the invention, the anti-HGF antibodiesdescribed herein, or HGF binding fragments thereof, as well ascombinations of said antibodies or antibody fragments, are administeredto a subject in a pharmaceutical formulation.

A “pharmaceutical composition” refers to a chemical or biologicalcomposition suitable for administration to a mammal. Such compositionsmay be specifically formulated for administration via one or more of anumber of routes, including but not limited to buccal, epicutaneous,epidural, inhalation, intraarterial, intracardial,intracerebroventricular, intradermal, intramuscular, intranasal,intraocular, intraperitoneal, intraspinal, intrathecal, intravenous,oral, parenteral, rectally via an enema or suppository, subcutaneous,subdermal, sublingual, transdermal, and transmucosal. In addition,administration can occur by means of injection, powder, liquid, gel,drops, or other means of administration.

In one embodiment of the invention, the anti-HGF antibodies describedherein, or HGF binding fragments thereof, as well as combinations ofsaid antibodies or antibody fragments, may be optionally administered incombination with one or more active agents. Such active agents includeanalgesic, antipyretic, anti-inflammatory, antibiotic, antiviral, andanti-cytokine agents. Active agents include agonists, antagonists, andmodulators of TNF-α, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-18,IFN-α, IFN-γ, BAFF, CXCL13, IP-10, VEGF, EPO, EGF, HRG, HepatocyteGrowth Factor (HGF), Hepcidin, including antibodies reactive against anyof the foregoing, and antibodies reactive against any of theirreceptors. Active agents also include 2-Arylpropionic acids,Aceclofenac, Acemetacin, Acetylsalicylic acid (Aspirin), Alclofenac,Alminoprofen, Amoxiprin, Ampyrone, Arylalkanoic acids, Azapropazone,Benorylate/Benorilate, Benoxaprofen, Bromfenac, Carprofen, Celecoxib,Choline magnesium salicylate, Clofezone, COX-2 inhibitors, Dexibuprofen,Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Ethenzamide, Etodolac,Etoricoxib, Faislamine, fenamic acids, Fenbufen, Fenoprofen, Flufenamicacid, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indometacin,Indoprofen, Kebuzone, Ketoprofen, Ketorolac, Lornoxicam, Loxoprofen,Lumiracoxib, Magnesium salicylate, Meclofenamic acid, Mefenamic acid,Meloxicam, Metamizole, Methyl salicylate, Mofebutazone, Nabumetone,Naproxen, N-Arylanthranilic acids, Oxametacin, Oxaprozin, Oxicams,Oxyphenbutazone, Parecoxib, Phenazone, Phenylbutazone, Phenylbutazone,Piroxicam, Pirprofen, profens, Proglumetacin, Pyrazolidine derivatives,Rofecoxib, Salicyl salicylate, Salicylamide, Salicylates,Sulfinpyrazone, Sulindac, Suprofen, Tenoxicam, Tiaprofenic acid,Tolfenamic acid, Tolmetin, and Valdecoxib. Antibiotics include Amikacin,Aminoglycosides, Amoxicillin, Ampicillin, Ansamycins, Arsphenamine,Azithromycin, Azlocillin, Aztreonam, Bacitracin, Carbacephem,Carbapenems, Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalothin,Cefalotin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefepime,Cefixime, Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil,Ceftazidime, Ceftibuten, Ceftizoxime, Ceftobiprole, Ceftriaxone,Cefuroxime, Cephalosporins, Chloramphenicol, Cilastatin, Ciprofloxacin,Clarithromycin, Clindamycin, Cloxacillin, Colistin, Co-trimoxazole,Dalfopristin, Demeclocycline, Dicloxacillin, Dirithromycin, Doripenem,Doxycycline, Enoxacin, Ertapenem, Erythromycin, Ethambutol,Flucloxacillin, Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin,Geldanamycin, Gentamicin, Glycopeptides, Herbimycin, Imipenem,Isoniazid, Kanamycin, Levofloxacin, Lincomycin, Linezolid, Lomefloxacin,Loracarbef, Macrolides, Mafenide, Meropenem, Meticillin, Metronidazole,Mezlocillin, Minocycline, Monobactams, Moxifloxacin, Mupirocin,Nafcillin, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin,Oxacillin, Oxytetracycline, Paromomycin, Penicillin, Penicillins,Piperacillin, Platensimycin, Polymyxin B, Polypeptides, Prontosil,Pyrazinamide, Quinolones, Quinupristin, Rifampicin, Rifampin,Roxithromycin, Spectinomycin, Streptomycin, Sulfacetamide,Sulfamethizole, Sulfanilimide, Sulfasalazine, Sulfisoxazole,Sulfonamides, Teicoplanin, Telithromycin, Tetracycline, Tetracyclines,Ticarcillin, Tinidazole, Tobramycin, Trimethoprim,Trimethoprim-Sulfamethoxazole, Troleandomycin, Trovafloxacin, andVancomycin. Active agents also include Aldosterone, Beclometasone,Betamethasone, Corticosteroids, Cortisol, Cortisone acetate,Deoxycorticosterone acetate, Dexamethasone, Fludrocortisone acetate,Glucocorticoids, Hydrocortisone, Methylprednisolone, Prednisolone,Prednisone, Steroids, and Triamcinolone. Any suitable combination ofthese active agents is also contemplated.

A “pharmaceutical excipient” or a “pharmaceutically acceptableexcipient” is a carrier, usually a liquid, in which an activetherapeutic agent is formulated. In one embodiment of the invention, theactive therapeutic agent is a humanized antibody described herein, orone or more fragments thereof. The excipient generally does not provideany pharmacological activity to the formulation, though it may providechemical and/or biological stability, and release characteristics.Exemplary formulations can be found, for example, in Remington'sPharmaceutical Sciences, 19^(th) Ed., Grennaro, A., Ed., 1995 which isincorporated by reference.

As used herein “pharmaceutically acceptable carrier” or “excipient”includes any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents that arephysiologically compatible. In one embodiment, the carrier is suitablefor parenteral administration. Alternatively, the carrier can besuitable for intravenous, intraperitoneal, intramuscular, or sublingualadministration. Pharmaceutically acceptable carriers include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. The use of such media and agents for pharmaceuticallyactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the active compound,use thereof in the pharmaceutical compositions of the invention iscontemplated. Supplementary active compounds can also be incorporatedinto the compositions.

Pharmaceutical compositions typically must be sterile and stable underthe conditions of manufacture and storage. The invention contemplatesthat the pharmaceutical composition is present in lyophilized form. Thecomposition can be formulated as a solution, microemulsion, liposome, orother ordered structure suitable to high drug concentration. The carriercan be a solvent or dispersion medium containing, for example, water,ethanol, polyol (for example, glycerol, propylene glycol, and liquidpolyethylene glycol), and suitable mixtures thereof. The inventionfurther contemplates the inclusion of a stabilizer in the pharmaceuticalcomposition. The proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.

In many cases, it will be preferable to include isotonic agents, forexample, sugars, polyalcohols such as mannitol, sorbitol, or sodiumchloride in the composition. Prolonged absorption of the injectablecompositions can be brought about by including in the composition anagent which delays absorption, for example, monostearate salts andgelatin. Moreover, the alkaline polypeptide can be formulated in a timerelease formulation, for example in a composition which includes a slowrelease polymer. The active compounds can be prepared with carriers thatwill protect the compound against rapid release, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers(PLG). Many methods for the preparation of such formulations are knownto those skilled in the art.

For each of the recited embodiments, the compounds can be administeredby a variety of dosage forms. Any biologically-acceptable dosage formknown to persons of ordinary skill in the art, and combinations thereof,are contemplated. Examples of such dosage forms include, withoutlimitation, reconstitutable powders, elixirs, liquids, solutions,suspensions, emulsions, powders, granules, particles, microparticles,dispersible granules, cachets, inhalants, aerosol inhalants, patches,particle inhalants, implants, depot implants, injectables (includingsubcutaneous, intramuscular, intravenous, and intradermal), infusions,and combinations thereof.

The above description of various illustrated embodiments of theinvention is not intended to be exhaustive or to limit the invention tothe precise form disclosed. The following examples are put forth so asto further provide those of ordinary skill in the art with a completedisclosure and description of how to make and use the subject invention,and are not intended to limit the scope of what is regarded as theinvention. Efforts have been made to ensure accuracy with respect to thenumbers used (e.g. amounts, temperature, concentrations, etc.) but someexperimental errors and deviations should be allowed for. Unlessotherwise indicated, parts are parts by weight, molecular weight isaverage molecular weight, temperature is in degrees centigrade; andpressure is at or near atmospheric.

EXAMPLES Example 1 Production of Enriched Antigen-Specific B CellAntibody Culture

Panels of antibodies are derived by immunizing traditional antibody hostanimals to exploit the native immune response to a target antigen ofinterest. Typically, the host used for immunization is a rabbit or otherhost that produces antibodies using a similar maturation process andprovides for a population of antigen-specific B cells producingantibodies of comparable diversity, e.g., epitopic diversity. Theinitial antigen immunization can be conducted using complete Freund'sadjuvant (CFA), and the subsequent boosts effected with incompleteadjuvant. At about 50-60 days after immunization, preferably at day 55,antibody titers are tested, and the Antibody Selection (ABS) process isinitiated if appropriate titers are established. The two key criteriafor ABS initiation are potent antigen recognition and function-modifyingactivity in the polyclonal sera.

Antibody Selection Titer Assessment

To identify and characterize antibodies that bind to huHGF, antibodycontaining solutions were tested by ELISA. Briefly, neutravidin coatedplates (Thermo Scientific), were blocked with ELISA buffer (0.1 mg/mLBSA, 1×PBS pH 7.4, 0.002% Tween 20 and 0.005% sodium azide) for 1 hr atroom temperature. The plates were then coated with a 1 μg/mLbiotinylated huHGF solution in ELISA buffer for 1 hour at roomtemperature. This was followed by a wash step (3× using PBS plus 0.05%Tween 20) and a second block with ELISA buffer. The recombinantantibodies were then added onto the plates and incubated for 1 hour atroom temperature and then washed 3× with PBS/Tween solution. Fordevelopment, an anti-rabbit Fc-HRP (1:5000 dilution in ELISA buffer) wasadded onto the wells and incubated for 45 min at RT. After a 3× washstep with PBS/Tween solution, the plate was developed using TMBsubstrate for 3 minutes, stopped using 0.5M HCl and read at 450 nm.

At the time positive antibody titers are established, animals aresacrificed and B cell sources isolated. These sources include: thespleen, lymph nodes, bone marrow, and peripheral blood mononuclear cells(PBMCs). Single cell suspensions are generated, and the cell suspensionsare washed to make them compatible for low temperature long termstorage. The cells are then typically frozen.

To initiate the antibody identification process, a small fraction of thefrozen cell suspensions are thawed, washed, and placed in tissue culturemedia. These suspensions are then mixed with a biotinylated form of theantigen that was used to generate the animal immune response, andantigen-specific cells are recovered using the Miltenyi magnetic beadcell selection methodology. Specific enrichment is conducted usingstreptavidin beads. The enriched population is recovered and progressedin the next phase of specific B cell isolation.

Example 2 Production of Clonal, Antigen-Specific B Cell-ContainingCulture

Enriched B cells produced according to Example 1 are then plated atvarying cell densities per well in a 96 well microtiter plate.Generally, this is at 50, 100, 250, or 500 cells per well with 10 platesper group. The media is supplemented with 4% activated rabbit T cellconditioned media along with 50K frozen irradiated EL4B feeder cells.These cultures are left undisturbed for 5-7 days at which timesupernatant-containing secreted antibody is collected and evaluated fortarget properties in a separate assay setting. The remaining supernatantis left intact, and the plate is frozen at −70° C. Under theseconditions, the culture process typically results in wells containing amixed cell population that comprises a clonal population ofantigen-specific B cells, i.e., a single well will only contain a singlemonoclonal antibody specific to the desired antigen.

Example 3 Screening of Antibody Supernatants for Monoclonal Antibody ofDesired Specificity and/or Functional Properties

Antibody-containing supernatants derived from the well containing aclonal antigen-specific B cell population produced according to Example2 are initially screened for antigen recognition using ELISA methods.This includes selective antigen immobilization (e.g., biotinylatedantigen capture by streptavidin coated plate), non-specific antigenplate coating, or alternatively, through an antigen build-up strategy(e.g., selective antigen capture followed by binding partner addition togenerate a heteromeric protein-antigen complex). Antigen-positive wellsupernatants are then optionally tested in a function-modifying assaythat is strictly dependent on the ligand. One such example is an invitro protein-protein interaction assay that recreates the naturalinteraction of the antigen ligand with recombinant receptor protein.Alternatively, a cell-based response that is ligand dependent and easilymonitored (e.g., proliferation response) is utilized. Supernatant thatdisplays significant antigen recognition and potency is deemed apositive well. Cells derived from the original positive well are thentransitioned to the antibody recovery phase.

Example 4 Recovery of Single, Antibody-Producing B Cell of DesiredAntigen Specificity

Antigen-specific B cells (produced according to Example 2 or 3), areisolated and used to clone antibody sequences as disclosed in thefollowing example. The cells may be used immediately or snap-frozen inan eppendorf PCR tube for storage at −80° C. until antibody sequencerecovery is initiated.

Example 5 Isolation of Antibody Sequences from Antigen-Specific B Cell

Antibody sequences are recovered using a combined RT-PCR based methodfrom a single isolated B-cell produced according to Example 4 or anantigenic specific B cell isolated from the clonal B cell populationobtained according to Example 2. Primers are designed to anneal inconserved and constant regions of the target immunoglobulin genes (heavyand light), such as rabbit immunoglobulin sequences, and a two-stepnested PCR recovery step is used to obtain the antibody sequence.Amplicons from each well are analyzed for recovery and size integrity.The original heavy and light chain amplicon fragments are cloned into anexpression vector and transformed into bacteria for plasmid propagationand production. Colonies are selected for sequence characterization.

Example 6 Recombinant Production of Monoclonal Antibody of DesiredAntigen Specificity and/or Functional Properties

Correct full-length antibody sequences for each well containing a singlemonoclonal antibody is established and miniprep DNA is prepared. ThisDNA is then used to transfect mammalian cells to produce recombinantfull-length antibody. Crude antibody product is tested for antigenrecognition and functional properties to confirm the originalcharacteristics are found in the recombinant antibody protein. Whereappropriate, large-scale transient mammalian transfections arecompleted, and antibody is purified through Protein A affinitychromatography. K_(D) is assessed using standard methods (e.g., surfaceplasmone resonance or biolayer interferometry) as well as IC50 in apotency assay.

Example 7 Preparation of Antibodies that Bind HuHGF

By using the antibody selection protocol described herein, a collectionof antibodies is generated that include those which exhibit potentfunctional antagonism of HGF. The antibodies elucidate a variety of HGFepitopes and thus may provide useful alternatives to, or adjunctivewith, antibodies that target previously identified HGF epitopes.

Example 8 ELISA Reactivity of Inventive Recombinantly Expressed Anti-HGFAntibodies

To characterize the inventive recombinantly expressed antibodies fortheir ability to bind to human HGF, antibody-containing solutions weretested by ELISA. All incubations were done at room temperature exceptcoating. Briefly, Immulon 4Hbx plates (Thermo Scientific) were coatedwith a HGF (R&D Systems, catalog number #294-HGN/CF) containing solution(1 ug/mL in PBS) overnight at 4° C. HGF coated plates were then washedthree times in wash buffer (PBS, 0.05% Tween-20). The plates were thenblocked using a blocking solution (PBS, 0.5% fish skin gelatin) forapproximately one hour. The blocking solution was then removed and theplates were then incubated with a dilution series of the antibody beingtested for approximately one hour. At the end of this incubation, theplate was washed three times with wash buffer and further incubated witha secondary antibody containing solution (Peroxidase conjugatedaffinipure F(ab′)2 fragment goat anti-human IgG, Fc fragment specific(Jackson Immunoresearch)) for approximately 45 minutes and washed threetimes. At that point a substrate solution (TMB peroxidase substrate,BioFx) and incubated for 3 to 5 minutes in the dark. The reaction wasstopped by addition of a HCl containing solution (0.5M) and the platewas read at 450 nm in a plate-reader.

The ELISA reactivity of antibodies according to the invention, i.e., ofAb1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25,and Ab28, determined as described herein, is contained in FIGS. 1-14.

Example 9 Determination of Affinity Constants of Inventive RecombinantlyExpressed Anti-HGF Antibodies Determination of Affinity Constants

The binding affinity of Ab8 and Ab10, was determined using a Fabfragment. For Ab12, a full-length antibody was used. Papain digestionswere conducted using immobilized papain (Thermo/Pierce) as permanufacturer's instructions. Briefly, purified antibodies were incubatedin a cystein/HCl-containing buffer with immobilized papain at 37° C.with gentle rocking. The digestion was monitored by taking an aliquotand analyzing using SDS-PAGE for cleavage of the heavy chain. To stopthe reaction, the immobilized papain was spun out and washed using 50 mMTris pH 7.5 and filtered. Undigested full length antibody and Fcfragments were removed by using a MabSelectSure (GE) column.

Binding affinities of monoclonal antibodies and antibody fragments forHGF were estimated using Bio-Layer Interferometry (BLI) on the Octet QK(ForteBio). Biotinylated antibody or antibody fragment was immobilized(1 ug/mL for 500 sec) onto the surface of Streptavidin (SA) Biosensors.A dilution series of human HGF (R&D Systems, catalog number #294-HGN/CF)prepared in 1× Kinetics Buffer (NaCl 0.0138 M; KCl 0.00027 M; 0.1 mg/mLBSA, 0.002% Tween and 0.005% Sodium Azide; pH 7.4, purchased fromForteBio) was used to query the antibodies. Multiple concentrations ofantigen (ranging from approximately 80 ng/mL to 640 ng/mL) were used.Association times of 15 minutes and dissociation times of 35 minuteswere used with the Octet Analysis Software (v3.1 ForteBio), to fitindividual sensor data using a 1:1 Langmuir binding model.

The kinetic binding values for Ab8, Ab10 and Ab12 to human-HGFdetermined as described above are contained in the Table below.

k_(d) (1/s) k_(a) (1/Ms) K_(D) (pM) Ab8 4.55E−05 3.73E+05 150 Ab105.13E−05 2.05E+05 250 Ab12 3.73E−05 2.76E+05 140

Example 10 Antitumor Activity of Inventive Recombinantly ExpressedAnti-HGF Antibodies In-vivo Evaluation

To study the antitumor efficacy of anti-HGF antibodies the ability ofanti-HGF antibodies, a subcutaneously implanted U-87MG human gliomaxenograft model was used. Five-week-old athymic NCr/nu/nu mice wereacclimated for 16 days and subsequently inoculated by sub-cutaneousinjection with U-87MG human glioma cells (ATCC, HTB-14, Lot #1653122)from in vitro cell culture. Each mouse received twenty million (2×10⁷)U-87MG glioma cells resuspended in 0.2 mL of MEM Eagles media. The cellcount and viability were determined with a Beckman Coulter VI CELL XRcell counter and viability analyzer. The day of tumor implantation wasdesignated as Day 0. Tumors were allowed to reach 162-294 mg in weight(162-294 mm³ in size) before the start of treatment. A sufficient numberof mice were implanted so that tumors in a weight range as narrow aspossible were selected for the trial on the day of treatment initiation(Day 18 after tumor implantation, designated as SD). Those animalsselected with tumors in the proper size range were assigned to thevarious treatment groups so that the median tumor weights on the firstday of treatment were as close to each other as possible.

Drug Treatment

For the antitumor and survival data corresponding to FIGS. 15 and 16,each group consisted of ten animals All test compounds were administeredby intraperitoneal (ip) injection every four days for two injections forfive weeks (Q4D×2/5 wks) at a dosage of 10 mg/kg/injection.

For the antitumor and survival data corresponding to FIGS. 17 and 18;and 19 and 20 respectively, each group again consisted of ten animals.All test compounds were administered by intraperitoneal (ip) injectionevery four days for two injections for five weeks (Q4D×2/5 wks) at adosage of 10 mg/kg/injection.

For the antitumor and survival data corresponding to FIGS. 21 and 22,each group again consisted of ten animals. All test compounds wereadministered by intraperitoneal (ip) injection every four days for twoinjections for five weeks (Q4D×2/5 wks). The dosage was 30, 10, or 2.5mg/kg/injection for Ab8 and Ab10. Dosage for the negative controlantibody was 30 mg/kg/injection.

Tumor Measurements and Body Weights

The subcutaneous tumors were measured and the animals were weighed twiceweekly starting the day of the first treatment. Tumor volume wasdetermined by caliper measurements (mm) and using the formula for anellipsoid sphere: L×W2/2=mm3, where L and W refer to the larger andsmaller perpendicular dimensions collected at each measurement. Thisformula is also used to calculate tumor weight, assuming unit density (1mm3=1 mg).

Study Duration

For the data corresponding to FIGS. 15 and 16, the in vivo study wasterminated 46 days after tumor implantation. Any animal found moribundor any animal whose tumor reached 4,000 mg, ulcerated, or was sloughedoff was euthanized prior to study termination. FIG. 15 provides theresponse of subcutaneous U-87MG glioma to treatment with a negativecontrol antibody, Ab10 or Ab12 (10 mg/kg/inj) obtained following theprotocol. FIG. 16 provides the survival proportions curve ofsubcutaneous U-87MG glioma treated with either a negative controlantibody, or Ab10 or Ab12 (10 mg/kg/inj) obtained following theprotocol.

For the antitumor and survival data corresponding to FIGS. 17, 18; and19 and 20, the in vivo study was terminated 79 days after tumorimplantation. Any animal found moribund or any animal whose tumorreached 4,000 mg, ulcerated, or was sloughed off was euthanized prior tostudy termination. FIG. 17 provides the response of subcutaneous U-87MGglioma to treatment with increasing doses of Ab8 (10, 2.5 and 0.25mg/kg/inj) and a negative control antibody (10 mg/kg/inj) FIG. 18provides the survival proportions curve of subcutaneous U-87MG gliomatreated with either increasing doses of Ab8 (10, 2.5 and 0.25 mg/kg/inj)or a negative control antibody (10 mg/kg/inj).

FIG. 19 provides the response of subcutaneous U-87MG glioma to treatmentwith increasing doses of Ab10 (10, 2.5 and 0.25 mg/kg/inj) and anegative control antibody (10 mg/kg/inj). FIG. 20 provides the survivalproportions curve of subcutaneous U-87MG glioma treated with eitherincreasing doses of Ab10 (10, 2.5 and 0.25 mg/kg/inj) or a negativecontrol antibody (10 mg/kg/inj).

For the data corresponding to FIGS. 21 and 22, the in vivo study wasterminated 80 days after tumor implantation. Any animal found moribundor any animal whose tumor reached 4,000 mg, ulcerated, or was sloughedoff was euthanized prior to study termination. FIG. 21 provides theresponse of subcutaneous U-87MG glioma to treatment with increasingdoses of Ab28 (30, 10, and 2.5 mg/kg/inj) and a negative controlantibody (30 mg/kg/inj) obtained following the protocol supra. FIG. 22provides the survival proportions curve of subcutaneous U-87MG gliomatreated with either increasing doses of Ab28 (30, 10, and 2.5 mg/kg/inj)or a negative control antibody (30 mg/kg/inj) obtained following theprotocol supra.

Example 11 Inhibition of c-Met Phosphorylation by InventiveRecombinantly Expressed Anti-HGF Antibodies

The c-met receptor has several phosphorylation sites, with uniquefunctions. Y1003 is in the juxtamembrane domain and recruits c-Cblprotein which is involved in ubiquitination of the receptor. It is saidto be a negative regulatory site. Y1234/35 is the major site. It isrequired for kinase activity and biological functions such as motilityand morphogenesis. Y1349 and Y1356 serve as the docking site forproteins like PI3K and PLC-γ.

To investigate the ability of Ab8 to inhibit human HGF directed Metphosphorylation, anti-phospho Met western blots were run as follows.Confluent cultures of prostate adenocarcinoma PC-3 cells (CRL-1435,ATCC, Manassas, Va.), previously maintained in growth medium (F-12K,#30-2004, ATCC Manassas, Va.) containing 10% FBS, (Hyclone, Victoria,Australia) were detached using 0.25% Trypsin (Hyclone, Logan, Utah) andseeded in 6 well plates at a density of 500,000 cells/well. Afterovernight incubation at 37° C., growth media was removed and cells wereserum starved overnight in medium with no FBS. Inhibition of human HGFdependent Met phosphorylation by Ab8 or a negative control antibody, wasdetermined by incubating 100 nM antibody and 1.25 nM HGF (Gibco LifeSciences, Cat. Number PH60254) in 15 ml conical tubes in serum freemedium for 1 h at 37° C., followed by addition to cells, another 10 minincubation at 37° C., removal of media, cold PBS rinse and cell lysiswith Tris lysis buffer (Cat #R6OTX-2, Meso Scale Discovery,Gaithersburg, Md.) supplemented with protease inhibitor cocktail(protease inhibitor, Cat #1836170, Roche, Indianapolis, Ind. plus 10 mMNaF), phosphatase inhibitor cocktail 1 (cat# P-2850, Sigma, St. Louis,Mo.) and phosphatase inhibitor cocktail 2 (cat# P-5726, Sigma, St.Louis, Mo.). Cell lysates were scraped from the 6-well plate and passedthrough a 23 g needle 5 times while incubating on ice. Approximately 20ug of total protein were loaded onto a 4-12% Bis-tris Nupage gel(Invitrogen, Carlsbad, Calif.) then transferred via iblot (Invitrogen,Carlsbad, Calif.). Nitrocellulose membranes were blocked with 3% BSA inTBS for 1 h at room temp with gentle shaking and incubated overnight at4° C. in 3% BSA in TBS+0.1% Tween-20, with one of the followingantibodies (Cell Signaling Technologies, Beverly, Mass.): Phospho-Met(Y1234/35) Rabbit mAb (Catalog #3129, Cell Signaling Technologies,Beverly, Mass.), Phospho-Met (Y1349) Rabbit mAb (Catalog #3133, CellSignaling Technologies, Beverly, Mass.), GAPDH XP Rabbit mAb (Catalog#5174, Cell Signaling Technologies, Beverly, Mass.) or affinity-purifiedRabbit Anti-phospho-HGF R/c-met (Y1003) antibody (Catalog # AF4059, R&DSystems, Minneapolis, Minn.). The nitrocellulose membrane was thenrinsed 3 times in PBS+0.05% Tween-20 and incubated at room temp 2 h in3% BSA in TBS+0.1% Tween-20+0.01% SDS containing peroxidase conjugatedaffinipure goat anti rabbit IgG, Fc fragment specific (#111-035-046,Jackson Immunoresearch, West Grove, Pa.) at 1:10,000 dilution. Thenrinsed 3 times as above. Finally, the membranes were developed for 5 minusing SuperSignal West Pico Chemiluminescent Substrate and exposed toX-ray film. The results in FIG. 23, show the inhibition of human-HGFdriven phosphorylation of Y1234/35, Y1003 and Y1349 of c-met using PC-3cells (prostate adenocarcinoma) by Ab8. The data therein show that Ab8shows inhibition of human HGF dependent Met phosphorylation at allsites, whereas the negative control does not alter c-metphosphorylation.

Example 12 Effect of Inventive Recombinantly Expressed Anti-HGFAntibodies on Cell Proliferation Proliferation Assay

The effect of anti-HGF antibodies according to the invention on cellproliferation in vitro was assayed. In these experiments, 4mBr-5 cells(rhesus monkey bronchial epithelial cell line) were obtained from ATCCand were used to characterize the inhibition of HGF driven cellproliferation by multiple antibody preparations. 4mBr-5 cells are afactor dependent cell line that proliferate when exposed to epidermalgrowth factor (EGF) or HGF.

4mBr-5 cells were grown in Ham's F-12K media supplemented with 10% FBSand 50 ng/ml recombinant human EGF (Gibco Life Technologies). The cellswere treated with 0.25% trypsin, washed twice with PBS and re-suspendedin Ham's F-12K media supplemented with 2.5% FBS (assay media). Celldensity was determined using Invitrogen's Countess Automated CellCounter. Cells at 200,000 cells/ml were seeded using 100 ul per wellinto a clear bottom black walled 96 well plate (Costar) and incubatedovernight. Assay media supplemented with 100 ng/ml HGF (Gibco LifeSciences, Cat. Number PH60254) was incubated in the presence of 10 μg/mlof either a negative control antibody or for 1 hour at 37° C. The mediawas removed and replaced with assay media alone which was subsequentlysupplemented with 100 ng/ml HGF, or 100 ng/ml HGF incubated in thepresence of the various antibodies. All conditions were performed intriplicate. Cells were allowed to proliferate for 48 hours. The mediawas removed and the cells washed twice with PBS. Cells were incubatedfor 30 minutes at 37° C. with 4 μg/ml Calcein AM (Invitrogen) andfluorescence read on a Molecular Devices SpectraMax M2 usingexcitation/emission maxima 490/520 nm.

FIGS. 24-37 respectively contain the results of these experiments. Asshown therein different anti-HGF antibodies according to the invention(Ab1, Ab2, Ab7, Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25and Ab28) inhibit proliferation of 4mBr-5 cells.

Example 13 Inhibition of Cell Invasion by Inventive RecombinantlyExpressed Anti-HGF Antibodies Cell Invasion Assay

The effect of anti-HGF antibodies according to the invention on cellinvasion was tested. In these experiments, DBTRG cells (humanglioblastoma cell line) were obtained from ATCC and were cultured inRPMI-160 supplemented with 10% FBS, L-glutamine (Hyclone), andnon-essential amino acids (Hyclone). Growth factor reduced Matrigelinvasion chambers (24 well plate, BD Biosciences) were hydrated with0.75 ml serum free RPMI-1640 in the lower chamber and 0.5 ml in theinsert. Chambers were incubated at 37° C. for 2 hours. The media wasremoved from both chambers and 0.75 ml serum free RPMI 1640 supplementedwith 0.1% BSA, and either 10 ng/ml HGF or 10 ng/ml HGF pre-incubatedwith 2 μg/ml of a negative control antibody or Ab8 for 30 minutes at 37°C. All conditions were performed in duplicate. DBTRG cells were removedfrom a plate with PBS supplemented using EDTA, pelleted bycentrifugation and washed twice with PBS. Cells were then added to theinsert chamber using 0.5 ml serum free media at a cell density of 20,000cells/ml. Chambers were incubated for 24 hours at 37° C. Afterincubation, the media was removed from the insert and non-invading cellsremoved with a cotton swab. Inserts were fixed and stained using aDiff-Quick stain kit (source). Membranes were removed from the inserts,air-dried and the invading cells counted by microscopy. As shown in FIG.38, Ab8 completely blocked DBTRG Matrigel invasion while the negativecontrol antibody had no effect on cell invasion.

CONCLUSION

Described herein are novel anti-HGF antibodies and antibody fragments,nucleic acids, compositions containing and methods of use thereof,especially therapeutic indications when used as a monotherapy or incombination with other therapies or active agents. While the embodimentsdisclosed herein are preferred, it will be appreciated to one of skillin the art that various alternative, modifications, variations orimprovements therein may be made by those skilled in the art, which areintended to be encompassed by the following claims.

The above description of various illustrated embodiments of theinvention is not intended to be exhaustive or to limit the invention tothe precise form disclosed. While specific embodiments of, and examplesfor, the invention are described herein for illustrative purposes,various equivalent modifications are possible within the scope of theinvention, as those skilled in the relevant art will recognize. Theteachings provided herein of the invention can be applied to otherpurposes, other than the examples described above.

These and other changes can be made to the invention in light of theabove detailed description. In general, in the following claims, theterms used should not be construed to limit the invention to thespecific embodiments disclosed in the specification and the claims.Accordingly, the invention is not limited by the disclosure, but insteadthe scope of the invention is to be determined entirely by the followingclaims.

The invention may be practiced in ways other than those particularlydescribed in the foregoing description and examples. Numerousmodifications and variations of the invention are possible in light ofthe above teachings and, therefore, are within the scope of the appendedclaims.

Certain teachings related to methods for obtaining a clonal populationof antigen-specific B cells were disclosed in U.S. Provisional patentapplication No. 60/801,412, filed May 19, 2006, the disclosure of whichis herein incorporated by reference in its entirety.

Certain teachings related to humanization of rabbit-derived monoclonalantibodies and preferred sequence modifications to maintain antigenbinding affinity were disclosed in International Application No.PCT/US2008/064421, corresponding to International Publication No.WO/2008/144757, entitled “Novel Rabbit Antibody Humanization Methods andHumanized Rabbit Antibodies”, filed May 21, 2008, the disclosure ofwhich is herein incorporated by reference in its entirety.

Certain teachings related to producing antibodies or fragments thereofusing mating competent yeast and corresponding methods were disclosed inU.S. patent application Ser. No. 11/429,053, filed May 8, 2006, (U.S.Patent Application Publication No. US2006/0270045), the disclosure ofwhich is herein incorporated by reference in its entirety.

Certain HGF antibody polynucleotides and polypeptides are disclosed inthe sequence listing accompanying this patent application filing, andthe disclosure of said sequence listing is herein incorporated byreference in its entirety.

The entire disclosure of each document cited (including patents, patentapplications, journal articles, abstracts, manuals, books, or otherdisclosures) in the Background of the Invention, Detailed Description,and Examples is herein incorporated by reference in their entireties.

1-160. (canceled)
 161. An anti-human hepatocyte growth factor (HGF)antibody or antibody fragment which specifically binds to the same oroverlapping epitope(s) and/or competes for binding to the same oroverlapping epitope(s) on an intact human HGF polypeptide or fragmentthereof as an anti-human HGF antibody selected from Ab1, Ab2, Ab7, Ab8,Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25, and Ab28. 162-164.(canceled)
 165. The anti-human HGF antibody or antibody fragmentaccording to claim 161, wherein said antibody or antibody fragmentcontains at least 2 complementarity determining regions (CDRs) of ananti-HGF antibody selected from the group consisting of Ab1, Ab2, Ab7,Ab8, Ab9, Ab10, Ab12, Ab14, Ab19, Ab21, Ab23, Ab24, Ab25 and Ab28.166-167. (canceled)
 168. The anti-human HGF antibody or antibodyfragment according to claim 161, wherein said antibody or antibodyfragment contains (a) a variable heavy (VH) chain comprising a CDR1sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO:44, SEQ ID NO: 244, SEQ ID NO: 284, SEQ ID NO: 324, SEQ ID NO: 364, SEQID NO: 444, SEQ ID NO: 524, SEQ ID NO: 724, SEQ ID NO: 804, SEQ ID NO:844, SEQ ID NO: 884, SEQ ID NO: 924, and SEQ ID NO:1044; a CDR2 sequenceselected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 46, SEQID NO: 246, SEQ ID NO: 286, SEQ ID NO: 326, SEQ ID NO: 366, SEQ ID NO:446, SEQ ID NO: 526, SEQ ID NO: 726, SEQ ID NO: 806, SEQ ID NO: 846, SEQID NO: 886, SEQ ID NO: 926, and SEQ ID NO:1046; and a CDR3 sequenceselected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 48, SEQID NO: 248, SEQ ID NO: 288, SEQ ID NO: 328, SEQ ID NO: 368, SEQ ID NO:448, SEQ ID NO: 528, SEQ ID NO: 728, SEQ ID NO: 808, SEQ ID NO: 848, SEQID NO: 888, SEQ ID NO: 928 and SEQ ID NO:1048; and/or (b) a variablelight (VL) chain comprising a CDR1 sequence selected from the groupconsisting of SEQ ID NO: 24, SEQ ID NO: 64, SEQ ID NO: 264, SEQ ID NO:304, SEQ ID NO: 344, SEQ ID NO: 384, SEQ ID NO: 464, SEQ ID NO: 544, SEQID NO: 744, SEQ ID NO: 824, SEQ ID NO: 864, SEQ ID NO: 904, SEQ ID NO:944, and SEQ ID NO:1064; a CDR2 sequence selected from the groupconsisting of SEQ ID NO: 26, SEQ ID NO: 66, SEQ ID NO: 266, SEQ ID NO:306, SEQ ID NO: 346, SEQ ID NO: 386, SEQ ID NO: 466, SEQ ID NO: 546, SEQID NO: 746, SEQ ID NO: 786, SEQ ID NO: 826, SEQ ID NO: 866, SEQ ID NO:906, SEQ ID NO: 946, and SEQ ID NO:1066; and a CDR3 sequence selectedfrom the group consisting of SEQ ID NO: 28, SEQ ID NO: 68, SEQ ID NO:228, SEQ ID NO: 268, SEQ ID NO: 308, SEQ ID NO: 348, SEQ ID NO: 388, SEQID NO: 468, SEQ ID NO: 548, SEQ ID NO: 748, SEQ ID NO: 828, SEQ ID NO:868, SEQ ID NO: 908, SEQ ID NO: 948, and SEQ ID NO:1068; with thefurther proviso that one or two residues of any of the afore-identifiedCDR polypeptides may be substituted with another amino acid, preferablya conservative amino acid substitution. 169-183. (canceled)
 184. Theanti-human HGF antibody or antibody fragment of claim 161, wherein: (a)the variable heavy and light chains are each at least 90% identical tothe variable heavy and light chains in SEQ ID NO: 2 and SEQ ID NO: 22,respectively; (b) the variable heavy and light chains are each at least90% identical to the variable heavy and light chains in SEQ ID NO: 42and SEQ ID NO: 62, respectively; (c) the variable heavy and light chainsare each at least 90% identical to the variable heavy and light chainsin SEQ ID NO: 242 and SEQ ID NO: 262, respectively; (d) the variableheavy and light chains are each at least 90% identical to the variableheavy and light chains in SEQ ID NO: 282 and SEQ ID NO: 302,respectively; (e) the variable heavy and light chains are each at least90% identical to the variable heavy and light chains in SEQ ID NO: 322and SEQ ID NO: 342, respectively; (f) the variable heavy and lightchains are each at least 90% identical to the variable heavy and lightchains in SEQ ID NO: 362 and SEQ ID NO: 382, respectively; (g) thevariable heavy and light chains are each at least 90% identical to thevariable heavy and light chains in SEQ ID NO: 442 and SEQ ID NO: 462,respectively; (h) the variable heavy and light chains are each at least90% identical to the variable heavy and light chains in SEQ ID NO: 522and SEQ ID NO: 542, respectively; (i) the variable heavy and lightchains are each at least 90% identical to the variable heavy and lightchains in SEQ ID NO: 722 and SEQ ID NO: 742, respectively; (j) thevariable heavy and light chains are each at least 90% identical to thevariable heavy and light chains in SEQ ID NO: 802 and SEQ ID NO:822,respectively; (k) the variable heavy and light chains are each at least90% identical to the variable heavy and light chains in SEQ ID NO: 842and SEQ ID NO: 862, respectively; (l) the variable heavy and lightchains are each at least 90% identical to the variable heavy and lightchains in SEQ ID NO: 882 and SEQ ID NO: 902, respectively; (m) thevariable heavy and light chains are each at least 90% identical to thevariable heavy and light chains in SEQ ID NO: 922 and SEQ ID NO: 942,respectively; or (n) the variable heavy and light chains are each atleast 90% identical to the variable heavy and light chains in SEQ ID NO:1042 and SEQ ID NO: 1062, respectively. 185-210. (canceled)
 211. Theanti-human HGF antibody or antibody fragment of claim 161, wherein: (a)the heavy chain comprises a sequence at least 80, 85, 90, 95, 96, 97,98, 99 or 100% identical to SEQ ID NO: 1 and the light chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 21; (b) the heavy chain comprises a sequence at least 80, 85,90, 95, 96, 97, 98, 99 or 100% identical to SEQ ID NO: 41 and the lightchain comprises a sequence at least 80, 85, 90, 95, 96, 97, 98, 99 or100% identical to SEQ ID NO: 61; (c) the heavy chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 241 and the light chain comprises a sequence at least 80, 85,90, 95, 96, 97, 98, 99 or 100% identical to SEQ ID NO: 261; (d) theheavy chain comprises a sequence at least 80, 85, 90, 95, 96, 97, 98, 99or 100% identical to SEQ ID NO: 281 and the light chain comprises SEQ IDNO: 301; (e) the heavy chain comprises SEQ ID NO: 321 and the lightchain comprises a sequence at least 80, 85, 90, 95, 96, 97, 98, 99 or100% identical to SEQ ID NO: 341; (f) the heavy chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 361 and the light chain comprises SEQ ID NO: 381; (g) theheavy chain comprises a sequence at least 80, 85, 90, 95, 96, 97, 98, 99or 100% identical to SEQ ID NO: 441 and the light chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 461; (h) the heavy chain comprises a sequence at least 80,85, 90, 95, 96, 97, 98, 99 or 100% identical to SEQ ID NO: 521 and thelight chain comprises SEQ ID NO: 541; (i) the heavy chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 721 and the light chain comprises SEQ ID NO: 741; (j) theheavy chain comprises a sequence at least 80, 85, 90, 95, 96, 97, 98, 99or 100% identical to SEQ ID NO: 801 and the light chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 821; (k) the heavy chain comprises a sequence at least 80,85, 90, 95, 96, 97, 98, 99 or 100% identical to SEQ ID NO: 841 and thelight chain comprises a sequence at least 80, 85, 90, 95, 96, 97, 98, 99or 100% identical to SEQ ID NO: 861; (l) the heavy chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 881 and the light chain comprises SEQ ID NO: 901; (m) theheavy chain comprises SEQ ID NO: 921 and the light chain comprises asequence at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% identical toSEQ ID NO: 941; or (n) the heavy chain comprises SEQ ID NO: 1041 and thelight chain comprises a sequence at least 80, 85, 90, 95, 96, 97, 98, 99or 100% identical to SEQ ID NO:
 1061. 212-224. (canceled)
 225. Theanti-human HGF antibody or antibody fragment of claim 161, wherein theantibody or antibody fragment is selected from the group consisting ofchimeric, humanized, human antibodies or antibody fragments, scFvs,camelbodies, nanobodies, IgNAR, Fab fragments, Fab′ fragments, MetMablike antibodies, monovalent antibody fragments, and F_((ab′)2)fragments.
 226. (canceled)
 227. The anti-human HGF antibody or antibodyfragment of claim 161, wherein the antibody or antibody fragmentsubstantially or entirely lacks N-glycosylation and/or O-glycosylation.228. The anti-human HGF antibody or antibody fragment of claim 161,wherein the antibody or antibody fragment comprises a human constantdomain.
 229. The anti-human HGF antibody or antibody fragment of claim228, wherein the antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. 230.The anti-human HGF antibody or antibody fragment of claim 161, whereinthe antibody or antibody fragment comprises an Fc region that has beenmodified to alter at least one of effector function, half-life,proteolysis, or glycosylation. 231-237. (canceled)
 238. The anti-humanHGF antibody or antibody fragment of claim 161, wherein the antibody orantibody fragment binds to HGF with a K_(D) that is less than about 100nM. 239-248. (canceled)
 249. A composition suitable for therapeutic,prophylaxis, or a diagnostic use comprising a therapeutically,prophylactically or diagnostically effective amount of at least oneantibody or antibody fragment according to claim 161, and optionallyanother active agent. 250-259. (canceled)
 260. The composition of claim249, wherein the other therapeutic agent comprising: chemotherapyagents, statins, cytokines, immunosuppressive agents, gene therapyagents, anti-coagulants, anti-cachexia agents, anti-weakness agent,anti-fatigue agent, anti-fever agent, anti-nausea agents, antiemeticagents, IL-6 antagonists, cytotoxic agents, analgesics, antipyretics,anti-inflammatory agents, antibiotics, antiviral agents, anti-cytokineagents, anti-angiogenesis agents, or any combination thereof. 261-278.(canceled)
 279. An isolated nucleic acid or nucleic acids which encodefor and when expressed in a suitable host cell result in the expressionof the anti-human HGF antibody or antibody fragment or the variableheavy or light chain thereof of claim
 161. 280-348. (canceled)
 349. Thenucleic acid or nucleic acids of claim 279, wherein said nucleic acid ornucleic acids which encode said antibody or antibody fragment comprise asequence encoding a VH and a VL region at least 80, 90, 95, 96, 97, 98,99 or 100% identical to SEQ ID NO: 12, SEQ ID NO: 32; SEQ ID NO: 52, SEQID NO: 72; SEQ ID NO: 252, SEQ ID NO: 272; SEQ ID NO: 292, SEQ ID NO:312; SEQ ID NO: 332, SEQ ID NO: 352; SEQ ID NO: 452, SEQ ID NO: 472; SEQID NO: 532, SEQ ID NO: 552, SEQ ID NO: 732; SEQ ID NO: 752; SEQ ID NO:812; SEQ ID NO: 832; SEQ ID NO: 852; SEQ ID NO: 872; SEQ ID NO: 892; SEQID NO: 912; SEQ ID NO: 932; SEQ ID NO: 952; SEQ ID NO:1052, and SEQ IDNO:1072; or a codon degenerate of any of the foregoing. 350-360.(canceled)
 361. A method of making the anti-human HGF antibody orantibody fragment according to claim 161, comprising expressing nucleicacids which encode for the expression of said anti-human HGF antibody orantibody fragment in a recombinant host cell. 362-370. (canceled)
 371. Amethod of treatment comprising administering least one anti-human HGFantibody or an antibody fragment thereof according to claim 161 to apatient in need thereof.
 372. The method of claim 371, wherein saidpatient has a disease or condition associated with HGF expressing cellsor the overexpression of HGF.
 373. The method of claim 371, wherein saidmethod results in one or more of inhibiting or blocking HGF-associatedangiogenesis, HGF-associated cell proliferation, HGF-associated cellinvasion, HGF-associated metastasis, the HGF/HGF-R (c-met) interaction,c-met activation, mitogenic, motogenic, and/or morphogenic properties ofHGF, HGF-associated cell scattering, and/or promoting HGF-associatedfibrosis.